Phosphoinositide-derived messengers in endocrine signaling

in Journal of Endocrinology

One of the fundamental questions in endocrinology is how circulating or locally produced hormones affect target cell functions by activating specific receptors linked to numerous signal-transduction pathways. An important subset of G protein-coupled cell-surface receptors can activate phospholipase C enzymes to hydrolyze a small but critically important class of phospholipids, the phosphoinositides. Although this signaling pathway has been extensively explored over the last 20 years, this has proven to be only the tip of the iceberg, and the multiplicity and diversity of the cellular functions controlled by phosphoinositides have surpassed any imagination. Phosphoinositides have been found to be key regulators of ion channels and transporters, and controllers of vesicular trafficking and the transport of lipids between intracellular membranes. Essentially, they organize the recruitment and regulation of signaling protein complexes in specific membrane compartments. While many of these processes have been classically studied by cell biologists, molecular endocrinology cannot ignore these recent advances, and now needs to integrate the cell biologist’s views in the modern concept of how hormones affect cell functions and how derailment of simple molecular events can lead to complex endocrine and metabolic disorders.

Abstract

One of the fundamental questions in endocrinology is how circulating or locally produced hormones affect target cell functions by activating specific receptors linked to numerous signal-transduction pathways. An important subset of G protein-coupled cell-surface receptors can activate phospholipase C enzymes to hydrolyze a small but critically important class of phospholipids, the phosphoinositides. Although this signaling pathway has been extensively explored over the last 20 years, this has proven to be only the tip of the iceberg, and the multiplicity and diversity of the cellular functions controlled by phosphoinositides have surpassed any imagination. Phosphoinositides have been found to be key regulators of ion channels and transporters, and controllers of vesicular trafficking and the transport of lipids between intracellular membranes. Essentially, they organize the recruitment and regulation of signaling protein complexes in specific membrane compartments. While many of these processes have been classically studied by cell biologists, molecular endocrinology cannot ignore these recent advances, and now needs to integrate the cell biologist’s views in the modern concept of how hormones affect cell functions and how derailment of simple molecular events can lead to complex endocrine and metabolic disorders.

Keywords:

Introduction

The mechanism of action of ‘Ca2+-mobilizing hormones’, a term introduced in the mid-1970s to denote hormones that exert their effects through generation of a cytosolic Ca2+ signal, was largely elucidated by the end of the 1980s (Fig. 1 and 2). The basic elements of this canonical signal-transduction cascade include the activation of the phospholipase C (PLC) β and γ isoforms by G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) respectively. Stimulation of these receptors generates two second messengers, the soluble Ins(1,4,5)P3 (InsP3) and the hydrophobic diacylglycerol from membrane, PtdIns(4,5)P2 (Berridge 1984). Once generated, the Ca2+-mobilizing messenger, InsP3, binds to specific receptors that are located mainly in the endoplasmic reticulum (ER) and function as tetrameric cation channels to release Ca2+ from intracellular Ca2+ stores (Mikoshiba 1997). This endogenous Ca2+ signal, in combination with increased Ca2+ influx via multiple Ca2+ entry mechanisms, activates numerous cytoplasmic and membrane-bound effector molecules with the help of Ca2+-binding proteins. Ca2+ is also taken up by mitochondria, where it stimulates metabolic enzymes (Hajnoczky et al. 1995) or initiates complex responses such as apoptosis (Pacher & Hajnoczky 2001). The other limb of this messenger system, diacylglycerol (DAG), directly activates several members of the protein kinase C family (Nishizuka 1988), and can also contribute to the direct regulation of some ion channels (Hardie 2003).

This elegantly simple concept marked only the beginning of an amazing explosion of research into phosphoinositides, and almost every component of the calcium-phosphoinositide messenger system has grown to become a research field of its own. The metabolism of InsP3 via both phosphorylation and sequential dephosphorylation revealed the identity of several inositol phosphate isomers (Shears 1998), as well as the InsP kinases (Verbsky et al. 2005) and phosphatases (Majerus et al. 1999). We are just at the beginning of understanding which of the numerous inositol phosphate isomers have regulatory functions. The discovery of phosphoinositide 3-kinases (PI3K) was the starting point in the recognition of the function of phosphoinositides as membrane-bound signaling molecules and was one of the main driving forces behind the search for proteins that are downstream targets of the inositol phospholipids. With the identification of new forms of inositol lipids and newly discovered functions of their classical forms, came the cloning of the multiple forms of inositide lipid kinases (Fruman et al. 1998) and phosphatases (Majerus et al. 1999), several of which have also been linked to human diseases (Pendaries et al. 2003) (Fig. 3). Research into the calcium aspect of InsP3- mediated signaling has also shown an enormous expansion, starting with the cloning of the InsP3 receptor (Furuichi et al. 1989, Mignery et al. 1989) and the continuing quest to identify the molecular entities behind the store-operated Ca2+ entry (SOC) pathway (Parekh & Putney 2005). There are several excellent reviews covering almost every aspect of inositide research from the viewpoint of the protein classes as indicated above. This review cannot be a compilation of all of these areas. Instead, it will aim to summarize recent advances and open questions from selected areas of endocrine research pointing to the inositol lipid angle within those areas. This is a selection with an inevitable bias and is by no means an indication that other aspects of inositides are not important in endocrinology. After all, it could be claimed that there are only two kinds of research: one in which phosphoinositides are already implicated and another where their involvement is yet to be recognized!

Receptor-mediated InsP3 formation and Ca2+ release

When Ca2+-mobilizing receptors engage their agonist ligands, the subsequent activation of PLC enzymes at the plasma membrane leads to rapid breakdown of PtdIns(4,5)P2. This process is both amplified and at the same time self-limited in a number of ways. It is amplified because of the positive regulation of PLC enzymes by cytoplasmic Ca2+, an effect that accounts for the profound impact of Ca2+ release on the extent of PtdIns(4,5)P2 hydrolysis (e.g. Horowitz et al. 2005). Without receptor activation, Ca2+ per se is much less potent, and only large cytoplasmic Ca2+ increases lead to PtdIns(4,5)P2 breakdown. Although all PLC enzymes are Ca2+-sensitive, the PLCδ1 enzyme appears to be largely responsible for Ca2+-mediated positive feedback on InsP3 generation (Rhee 2001). At the same time, the process of InsP3 formation is limited because most GPCRs undergo homologous desensitization that limits their ability to activate G-proteins (Luttrell & Lefkowitz 2002). Moreover, both GPCRs and RTKs undergo ligand-induced endocytosis and are rapidly removed from the plasma membrane, whence they can also be quickly recycled and reappear during resensitization (Gaborik & Hunyady 2004). PtdIns(4,5)P2 hydrolysis is also limited because, as a result of its relatively low level in the membrane, it has to be replenished by the sequential actions of PI 4- and PIP 5-kinases on the larger pools of PtdIns. Even the larger pool of plasma membrane PtdIns can become depleted if not maintained by supply from the ER by PI transfer proteins (Fig. 1).

Which inositol lipid pools participate in the classical signaling cascade and which enzymes are primarily responsible for their generation?

The existence of hormone-sensitive and insensitive pools of phosphoinositides has been described in early research using metabolic labeling with myo-inositol (Koreh & Monaco 1986). Recent studies have indicated that PtdIns(4,5)P2 is produced by two different pathways: in the canonical pathway, it is formed through PtdIns(4)P by sequential phosphorylations by PI 4-kinases (Balla 1998) and the type I PIP kinases (or PIP5Ks) (Hinchliffe et al. 1998). In a recently recognized pathway, PtdIns(4,5)P2 synthesis proceeds via PtdIns(5)P that is phosphorylated by type-II PIP kinases (or PIP4Ks) (Rameh et al. 1997) (Fig. 3). Since each group of enzymes has multiple forms that are located in distinct cellular compartments, it is inevitable that phosphoinositides will be generated in different types of membranes. Which of these inositide pools are linked to hormone action? It is widely assumed that hormonal stimulation leads to breakdown of the plasma membrane PtdIns(4,5)P2 pool, and this has been substantiated by the use of green fluorescent protein (GFP)-fused pleckstrin homology (PH) domains that recognize the lipid in the plasma membrane. However, PtdIns(4,5)P2 pools also exist in other membrane locations, such as the Golgi, the ER and the nucleus (Watt et al. 2002), and PLC enzymes are also found at these sites (Rebecchi & Pentyala 2000). Therefore, it is not unreasonable to assume that PLC activation – either direct, or mediated by the cytoplasmic Ca2+ increase – occurs at intracellular membranes and contributes to InsP3 and DAG generation at those sites with local consequences.

Equally important is the simple question of whichenzymes generate the PI(4,5)P2 that is subject to receptor-controlled PLC-mediated hydrolysis. Recently, it was shown that human PIP 5-kinase γ is the enzyme that is necessary for GPCR-mediated InsP3 formation and Ca2+ signaling (Wang et al. 2004). In contrast, mouse PIP 5-kinase Iβ (identical to human PIP5KIα), recruited by Bruton’s tyrosine kinase, enhances Ca2+ signaling in B cells (Saito et al. 2003). Stimulation of PIP 5-kinase activity by small guanosine triphosphate (GTP)-binding proteins has been well documented (Chong et al. 1994, Honda et al. 1999), but it is not known whether receptor-mediated activation of PIP 5-kinase activity occurs. A very rapid increase in PtdIns(4,5)P2 level after stimulation has been recently demonstrated, suggesting direct activation of PtdIns(4,5)P2 synthesis (Xu et al. 2003). Less clear is the identity of the PI 4-kinase or kinases that provide PtdIns(4)P for the PIPKs. Hormone-sensitive PtdIns(4)P pools have been shown to be generated by the type-III PI4Ks (which are sensitive to higher concentrations of PI3K inhibitors) (Nakanishi et al. 1995). However, neither the PI4 KIIIα nor -β isoform is detectable at the plasma membrane of mammalian cells; instead, these isoforms are located in ER and Golgi membranes respectively (Wong et al. 1997). Yet, recent studies have shown that a plasma membrane (PM) pool of PtdIns(4)P is generated by PI4 KIIIα (Balla et al. 2005), raising the question of whether the lipid is generated at the PM by a small fraction of the enzyme or is generated elsewhere and transported to the PM. There is little direct evidence that PI4K activities are stimulated during receptor activation, and only PI4 KIIβ has been shown to be activated by a Rac-dependent mechanism (Wei et al. 2002).

As mentioned above, the maintenance of PtdIns(4,5)P2 pools also requires the function(s) of the family of PI transfer proteins (PITPs). These proteins transfer PtdIns and PtdCho between membranes and are necessary for maintenance of the PLC-sensitive phosphoinositide pools (Thomas et al. 1993). PITPs also exist in several forms, of which the soluble PITPα and PITPβ isoforms have non-overlapping functions that reach far beyond the regulation of hormone-sensitive phosphoinositide pools, affecting both phospholipid synthesis and vesicular trafficking. This function of lipid-transfer proteins will be further detailed below.

How does InsP3 regulate Ca2+ release?

Since the isolation and cloning of the InsP3 receptor channels, impressive progress has been made in understanding their functions. All three isoforms of the InsP3 receptor (types I, II and III) function as intracellular Ca2+ channels that operate as a homo- or heterotetramer (Mikoshiba 1993). Each receptor subunit has a channel portion containing six transmembrane helices and a pore domain located between TM5 and TM6, close to the C-terminus of the protein (Maeda et al. 1991, Galvan et al. 1999, Patel et al. 1999). The ligand-binding domain (LBD) of the receptor is located at the N-terminus (Mignery & Sudhof 1990) and is separated from the channel domain by a long intervening regulatory region facing the cytoplasm (Mignery & Sudhof 1990, Mikoshiba 1993). InsP3 binding leads to rapid activation of the channel, but Ca2+-induced Ca2+ release, similar to that featured in the related ryanodine receptors (RyR), is also an important regulatory mechanism of IP3Rs (Taylor & Laude 2002). Because of their ER location, little is known about the gating mechanism and properties of IP3R channels. The only electrophysiologic data are derived from isolated channels reconstituted in lipid bilayers (Bezprozvanny et al. 1991) or from patch-clamp recordings of the nuclear envelope (Mak & Foskett 1994). Most of our knowledge of the behavior of the intact channels is inferred from measurements of Ca2+ (or other cation) fluxes. These studies have provided invaluable information about the InsP3 and Ca2+ regulation of the channel (Bezprozvanny et al. 1991, Hajnoczky & Thomas 1994), but no molecular mechanisms or states have been correlated with channel behavior. One major question is how the N-terminal LBD can regulate the channel itself. Recent evidence suggests that the C-terminal channel domain and the N-terminal LBD are in very close molecular proximity, and that the ligand-induced conformational change within the LBD could be transferred to the channel domain itself (Boehning & Joseph 2000). The recently solved X-ray structure of the LBD (Bosanac et al. 2002) and the adjacent N-terminal inhibitory domain (Bosanac et al. 2005) has helped to clarify the structural basis of InsP3 binding, and, together with high-resolution electron microscopy and 3-D reconstruction of the channel structure (Jiang et al. 2002, da Fonseca et al. 2003, Sato et al. 2004), should advance our understanding of the gating mechanism of the protein.

The positioning of ER membranes containing InsP3 receptors relative to other membranes, and the interaction of the receptor with other proteins, add to the complexity of Ca2+ regulation in local compartments (Fig. 2). Early fractionation studies suggested that InsP3 receptors could be isolated from ‘mitochondrial’ (Dawson & Irvine 1984) and ‘plasma membrane’ (Guillemette et al. 1988) fractions, indicating ER contamination of these fractions enriched in InsP3 receptors. Recent evidence has shown the existence of a special ER–mitochondria interface (Rizzuto et al. 1993) and a very close ‘quasi-synaptic’ functional coupling between InsP3 receptor-mediated Ca2+ release and mitochondrial Ca2+ uptake (Csordas et al. 1999). Moreover, the physical association of InsP3 receptors with TRPC3 channels at the plasma membrane could provide the basis for Ca2+ influx regulation linked to InsP3-induced Ca2+ release (Kiselyov et al. 1998). These observations raise the question of whether the InsP3R could serve as a structural participant in the tethering of the ER to other membranes in the proximity of the channel. It has also been suggested that the LBD of the InsP3R binds to PtdIns(4,5)P2 of the plasma membrane in quiescent cells when InsP3 levels arelow (Glouchankova et al. 2000), and that changing PtdIn(4,5)P2 together with increased InsP3 could also participate in the regulation of these channels.

Cell-surface receptors and PI3K-mediated signaling

The classical activation mechanism of PI3Ks was identified by studies on receptor tyrosine kinases and on soluble and oncogenic tyrosine kinases (Otsu et al. 1991). In these systems, the p85 regulatory subunit associates with tyrosine-phosphorylated target sequences through its SH2 domains, recruiting the cytoplasmic PI3Kα or -β catalytic subunit to the membrane. The p85 subunit becomes tyrosine phosphorylated during this process, leading to increased activity of the kinase. Less is known about the mechanism of PI3K activation in the case of GPCRs. In hematopoietic cells, where PI3Kγ is found in significant amounts, activation via the βγ-subunits of Gi/Go proteins is the main activation pathway (Stephens et al. 1994). This is mediated by associated p101 (Stephens et al. 1997) or p84 (Suire et al. 2005) regulatory subunits, but direct regulation of the PI3Kγ enzyme by βγ-subunits has also been reported (Leopoldt et al. 1998). Much less clear and more controversial is the manner in which PI3K is activated by GPCRs in tissues where PI3Kγ is not expressed, or is present only at low levels. In many cases, activation occurs by transactivation of receptor tyrosine kinases (Daub et al. 1996) followed by the above-detailed mechanism, but this is not the sole means by which GPCRs activate PI3Ks. It is also not known what determines which of the class I PI3Ks (α,β,δ) is activated and which splice form of the p85/p55 regulatory subunit associates with them. Deletion of either PI3Kα or β is lethal (Bi et al. 1999, 2002), as is the elimination of all the splice forms of the p85/55α subunits (Fruman et al. 2000), but not of the p85α form alone (Terauchi et al. 1999), indicating a level of complexity that is still far from being understood. Impairment of PI3K signaling has prominent effects on insulin signaling (Terauchi et al. 1999), and recent studies indicate that the stochiometry between the p85 and p110 subunits, together with the direct interaction of the free p85 subunit with IRS-1, is a major factor determining the insulin responsiveness of the cells (Luo et al. 2005).

Activation of PI3K by estrogens via ligand-dependent association of ERα with the p85 regulatory subunit has been demonstrated (Simoncini et al. 2000). More recently, a heptahelical receptor, GPR30, which is located in the ER, was shown to respond to estrogen stimulation, leading to the activation of PI3K in the nucleus, as indicated by the translocation of the Akt PH-domain to the nucleus (Revankar et al. 2005). Many questions remain to be answered about this intriguing effect, but it appears to be a new paradigm in steroid hormone action that is not mediated by the classical nuclear receptors.

The main downstream signaling pathway from PI3Ks proceeds via the Akt protein kinase (Franke et al. 1997) and its upstream regulator kinase, PDK1 (Alessi et al. 1997). These kinases are master regulators of a whole range of cellular processes related to glucose metabolism, protein synthesis and cell division, and also represent the main antiapoptotic pathway. Detailed coverage of these processes in endocrine and metabolic regulation is beyond the scope of this review, but can be found elsewhere (Mora et al. 2004).

Receptor trafficking and its regulation by phosphoinositides

Many cell-surface receptors undergo ligand-induced endocytosis mostly (but not exclusively) by a clathrin-mediated internalization process that shares many of the characteristics of the endocytosis and recycling of nutrient receptors (Brown & Goldstein 1979). The sorting of the receptors into clathrin-coated pits is mediated by interaction of the receptor with clathrin-adapter proteins. Several adapter proteins have been identified, including the tetrameric adapters, AP-(2–4), the monomeric adapters such as AP-180 (or its nonneural form, CALM), the Dab1/ARH and the GGA proteins. Many of these adapters exert their effects at intracellular membranes (Owen et al. 2004), when they recognize specific sequences (sorting motifs) within the intracellular segments of nutrient receptors or RTKs. They also bind to clathrin, thereby bringing the receptors to the site of clathrin assembly (Fig. 4). Several sorting motifs have been identified in receptors, some containing Tyr, such as the NPxY or the YxxΦ sequences, and others containing Leu/Ile residues, such as the D/ExxxL/I or DxxLL motifs (Bonifacino & Traub 2003). In the case of GPCRs, the common adapter proteins are β-arrestins which bind to GPCR tails that are Ser/Thr phosphorylated by G protein receptor kinases (GRKs) (Lefkowitz 1993). Phosphorylation of GPCR tails by GRKs is greatly facilitated by the binding of agonist ligands, and it accounts for the ligand-dependence of GPCR internalization. The role of receptor internalization is obvious in the case of nutrient receptors but is less clear in the case of hormone receptors. For this latter, it is an important mechanism for regulating the number of available receptors on the cell surface, and it also eliminates activated receptors that often undergo degradation (Dikic 2003). There is also increasing evidence that some internalized receptors may continue to signal in the endocytic compartments (Luttrell & Lefkowitz 2002).

It is quite remarkable that many of the proteins that participate in the internalization process contain binding sites for phosphoinositides. With the exception of the GGAs, all of the above-mentioned clathrin-adapter proteins have been shown to contain one or more phosphoinositide-binding motifs (Owen et al. 2004). Some GRKs (such as GRK2 and 3) contain a pleckstrin-homology domain that is important for the membrane recruitment of the enzymes (Pitcher et al. 1998), but the phospholipid species involved in their regulation is not yet known (Carman et al. 2000). Recently, β-arrestins were shown to contain phosphoinositide-binding regions that are important for GPCR internalization (Gaidarov et al. 1999, Lee et al. 2003). Finally, the GTP-binding protein, dynamin, which is critical for pinching off internalized vesicles from the plasma membrane, is also known to contain a PH domain. In this case, mutation of the residues essential for lipid binding has a dominant negative effect on receptor endocytosis (e.g. Lee et al. 1999). From the presence of these domains in the above proteins and their ability to bind phosphoinositides in vitro, it is widely assumed that phosphoinositides regulate receptor endocytosis. Mutagenesis studies targeting the lipid-binding regions of the proteins support this assumption, but few studies are available on the question of whether modifying lipid production would affect receptor trafficking. Wortmannin-sensitive (i.e., type III PI4K-synthesized) PtdIns(4)P and PtdIns(4,5)P2 pools support muscarinic and β2-adrenergic receptor endocytosis (Sorensen et al. 1998), and the plasma membrane recruitment of AP-2 protein and transferrin receptor endocytosis correlates with PIP5KIβ activity (Padron et al. 2003). In general, it is not certain which phosphoinositide species regulates any particular step in the complex process of endocytosis. Because of its abundance and in vitro binding to many of the above domains, PtdIns(4,5)P2 is considered the most important inositide in receptor endocytosis. Although several reports have indicated that PI 3-kinases are also agents in this process (Joly et al. 1994, Naga Prasad et al. 2002), pharmacologic blockade of PI3Ks does not dramatically influence the early steps of receptor internalization (Hunyady et al. 2002). Most recently, the protein kinase activity of PI3Kγ via phosphorylation of tropomyosin was shown to be critical for β-adrenergic receptor endocytosis (Naga Prasad et al. 2005).

Fate of the internalized receptors

It is also well documented that the subsequent fate of internalized receptors is highly dependent on processes regulated by PI3Ks. After reaching early endosomes, a large proportion of receptors recycle back to the plasma membrane via a vesicular mechanism involving Rab4 and Rab5 GTPases (Seachrist et al. 2000, Hunyady et al. 2002, Dale et al. 2004). This rapid recycling process is inhibited by the PI 3-kinase inhibitors, wortmannin and LY294002, leading to the accumulation of the receptors in large endocytic vesicles (Shpetner et al. 1996, Hunyady et al. 2002). A fraction of the transferrin receptors and some GPCRs are also sorted into another compartment, called recycling endosomes, that is positive for Rab11 GTPase, and from which there is a significantly slower recycling to the cell surface by a process more resistant to PI 3-kinase inhibitors (Hunyady et al. 2002, van Dam et al. 2002). Interestingly, a group of GPCRs very rapidly recycle back to the cell surface after internalization, and these receptors are not sorted into, and do not take β-arrestin, to ‘deeper’ compartments (Zhang et al. 1999). One of the most exciting ‘organelles’ of the internalization and recycling pathway is the multivesicular body (MVB), a site for molecular decisions on whether receptors recycle or undergo degradation. Ubiquitination of receptors often determines their fate. Mono-ubiquitination (sometimes at multiple sites) has been shown to be important for internalization and targeting of activated RTKs, such as the EGFR to the inner membrane of the MVB and subsequent lysosomal degradation (Hicke 2001, Katzmann et al. 2002, Haglund et al. 2003). This process is to be distinguished from poly-ubiquitination (where the added ubiquitin is further ubiquitinated multiple times) of soluble proteins that are targeted for proteasomal degradation (Bonifacino & Weissman 1998), although the distinction between the two kinds of ubiquitination is not always clear. Unlike transferrin receptors, some GPCRs also appear at the MVB during their recycling or degradation (Hunyady et al. 2002), and also have been shown to be ubiquitinated (Marchese & Benovic 2001, Shenoy et al. 2001). The role and significance of GPCR ubiquitination in the endocytic and recycling process is not as well understood as for RTKs. 3-Phosphorylated inositides are principal regulators of the sorting process along the endocytic pathway. Class III PI3Ks generate PtdIns(3)P, which contributes to the recruitment to endocytic vesicles of proteins containing FYVE, or PX domains such as Hrs or sorting nexins, respectively. These proteins are important in cargo selection and vesicle dynamics. PtdIns(3)P is also converted to PtdIns(3,5)P2 by the PIKfyve enzyme (Shisheva et al. 1999) (also termed type III PIP kinase). In Saccharomyces cerevisiae, this kinase, termed Fab1p, is also needed for protein sorting into the MVB (Odorozzi et al. 1998).

These selected examples illustrate the complexity of the phosphoinositide requirement of the endocytic and sorting process, and highlight the magnitude of the task that remains to be completed in clarifying the molecular details and biologic importance of receptor endocytosis in endocrine functions.

Phosphoinositides and ion channels

The relationship between phosphoinositide turnover and Ca2+ signaling has long been firmly established, and for a while the only debate was about which was the consequence of the other (Cockcroft 1981, Michell 1982). However, the discovery of InsP3-mediated Ca2+ release from internal pools has clarified the primary connection between them. Importantly, Ca2+ also enters the cells via Ca2+ channels located in the plasma membrane, and initially a distinction was made between voltage-gated Ca2+ channels, which mostly regulate the functions of ‘excitable’ cells, and non-voltage-gated Ca2+ influx pathways (or receptor-regulated Ca2+ channels) working in nonexcitable and endocrine cells. Although this distinction has not persisted very long (e.g., the presence of voltage-gated Ca2+ channels in endocrine cells has become common knowledge), the molecular entities behind the Ca2+ entry mechanism(s), described as ‘capacitative’ Ca2+ entry pathway or store-operated Ca2+ entry (SOC) (Putney 1986), has remained elusive.

All nonexcitable cells display increased Ca2+ influx that falls within the criteria of capacitative or SOC, after activation by a ‘calcium-mobilizing’ stimulus (Putney 1986). After decades of studies to identify the Ca2+ channels that underlie this phenomenon, it is still questionable whether a single molecular entity is responsible for the enhanced Ca2+ influx observed after emptying of the intracellular Ca2+ stores (Parekh & Putney 2005). The current activated by the release of Ca2+ stores is termed ICRAC (calcium release-activated current) (Hoth & Penner 1992), but its molecular equivalent is still unresolved, as is the question of whether ICRAC is ‘the current’ corresponding to SOC (see Parekh & Putney (2005) for an excellent recent review). The Ca2+ channel underlying the Drosophila transient receptor potential (Trp) in the fly photoreceptor was proposed to be a channel corresponding to SOC (Wes et al. 1995). After cloning of the mammalian homologs of these proteins (TrpC1–7, ‘C’ stands for classical), a large number of studies addressed this question. Of the seven TrpC channels, most data were gathered for TrpC1 and TrpC3 channels. Overexpression of TrpC1 channels yields a nonselective Ca2+-permeable conductance that moderately increases Ca2+ influx after store depletion in some studies (Zhu et al. 1996), but not in others (Lintschinger et al. 2000). This discrepancy could be due to the fact that TrpC1 proteins require coexpression of other Trp channels (such as TrpC4 and -5) to traffic properly to the plasma membrane (Strubing et al. 2001). Downregulation or elimination of TrpC1 channels at the cellular level also indicates that they are at least partially responsible for store-operated Ca2+ influx (Liu et al. 2003) and ICRAC (Mori et al. 2002).

Studies on TrpC3 channels provided additional insights into the connection between Ca2+ release and influx. Early studies suggested that these channels are regulated by Ca2+ and diacylglycerol (and thereby responded to agonist stimulation), but not by store depletion (Lintschinger et al. 2000). However, other studies have shown that TrpC3 channels do respond to store depletion and that they physically interact with InsP3 receptors, providing experimental support for the previously hypothetical conformational-coupling model of SOC (Kiselyov et al. 1998). It is very likely that Trp channel behavior depends on the presence of other Trp channels (or of associated proteins) in a particular cell, and that cells display a great variety of Ca2+ influx characteristics, depending on the composition of the molecular complex responsible for the store-operated influx phenomenon in specific cell types. This may explain why overexpression studies with the various Trp channels yield apparently discordant information. A detailed, up-to-date review of all Trp channels is given by Putney (2004). Very recent data identify STIM1, an ER-resident, single-transmembrane protein with a Ca2+-sensing luminal domain, as a critical component of SOC (Liou et al. 2005, Roos et al. 2005). STIM1 is not a channel itself, but it may finally provide us with a thread from which the SOC phenomenon will be deciphered. There is very little information about direct regulation of TrpC channels by phosphoinositides, but findings with members of other Trp channel families (see below) indicate that this question should be further investigated.

Curiously, the first ion channels for which phosphoinositide regulation was described were not Ca2+ channels, but members of the inwardly rectifying (Kir) potassium channel family (Hilgemann & Ball 1996). Some Kir channels were shown to be regulated by the βγ-subunits of heterotrimeric G proteins (GIRKs) (Krapivinsky et al. 1995) and PtdIns(4,5)P2 (Huang et al. 1998, Zhang et al. 1999) and became the prototypical examples. A number of studies followed that showed phosphoinositide regulation of other ion channels. These included other potassium channels, such as the M-current (Suh & Hille 2002) and the underlying KCNQ channels (Zhang et al. 2003), and the two-pore domain K+ channels (Chemin et al. 2005, Lopes et al. 2005). Among Ca2+ channels, members of the Trp family (other than TrpCs) have been shown to be regulated by PtdIns(4,5)P2. As shown for the TrpM5, -7 and -8 channels, PtdIns(4,5)P2 is necessary for channel activity (Runnels et al. 2002). In the case of TrpM8, both cooling and addition of activator ligands, such as menthol, alter the lipid affinity of the channel. The region responsible for lipid regulation has been mapped within the so-called Trp-domain (Rohacs et al. 2005). Other Trp channels, such as the vanilloid receptor (TrpV1), are also regulated by PtdIns(4,5)P2 (Chuang et al. 2001), and this lipid was found to be essential for the recovery of the TrpV1 channel from desensitization (Liu et al. 2005). The intimate relationship between some of these channel proteins and PLC enzymes strongly suggests that the Ca2+ that enters via Trp channels controls local PtdIns(4,5)P2 levels, thereby regulating channel activity by a local feedback regulation. Whether this local control is a general principle governing the function of other Trp channels, including the ‘classical’ TrpC channels discussed above, remains to be determined.

A further emerging theme in Ca2+ (and other) channel control is that channels located in intracellular membrane compartments are inserted into the plasma membrane by a regulated process quite reminiscent of the GLUT4 glucose transporter insertion into the plasma membrane after insulin stimulation. It has been recently shown that growth factors enhance the insertion of TrpC5 channels from a vesicular pool by a PI3K- and Rac1-mediated mechanism that also involves PIP5KIα (Bezzerides et al. 2004). Similarly, PI3K-dependent trafficking of voltage-gated Ca2+ channels to the plasma membrane has been recently reported (Viard et al. 2004). Intriguingly, a previously described curious stimulatory effect of PLCγ1 expression on the activity of TrpC3 channels (that oddly did not require the PLC activity of the protein) has also been attributed to enhanced surface expression of the channels (Patterson et al. 2002). In this newly discovered process, one of the 1/2 PH-domains of PLCγ1 and a half-PH domain located within the intracellular tails of TrpC channels form an ‘intermolecular PH domain’ providing phosphoinositide interaction and stabilizing the channel at the plasma membrane (van Rossum et al. 2005). These new observations demonstrate that, in addition to the acute regulation of channel activities in the plasma membrane by rapid changes in phosphoinositides, these lipids also control the trafficking and distribution of the channels between the various membranes, adding a new level of complexity to the control of Ca2+ (and other ion) fluxes of the cell.

Phosphoinositides and exocytosis

While regulated secretion is one of the key features of many endocrine and neuroendocrine cells, it is also found in other cells such as those of the immune system. This process is also called dense-core vesicle (DCV) exocytosis to distinguish it from the small synaptic vesicle (SV) exocytosis found in presynaptic terminals, although the underlying processes have many common features (Martin 2003, Wenk & De Camilli 2004). DCVs containing cargo to be secreted undergo maturation that increases their competence to dock, and ultimately fuse, with the plasma membrane when a rapid rise in Ca2+ concentration triggers the fusion process. Some of the mature granules under the membrane will dock to the plasma membrane, but these predocked vesicles still have to undergo ‘priming’ to become the ‘readily releasable pool’ that is first to be fused upon stimulation (Fig. 5). The prefusion process of ‘priming’ has been shown to be ATP-dependent and to involve the synthesis of PtdIns(4,5)P2 (Eberhard et al. 1990, Hay & Martin 1993, Hay et al. 1995). Purification of the cytosolic components required for ATP-dependent priming has led to the identification of the PI-transfer protein (Hay & Martin 1993) and a PIP 5-kinase (Hay et al. 1995), but the PI4K that is needed for PtdIns(4,5)P2 generation has never been identified. It is noteworthy that the first successful cloning of the type II PI4K resulted from the purification of a chromaffin granule-associated PI4K (Barylko et al. 2001). Whether this enzyme supports the process of exocytosis is yet to be determined.

The PI3K inhibitor, wortmannin (Wm), potently inhibits the degranulation caused by FcR activation in rat basophilic leukaemia (RBL) cells at concentrations that are consistent with inhibition of PI3K enzymes (Yano et al. 1993). However, in other cells, such as pituitary gonadotrophs (Rao et al. 1997), pancreatic β cells (Straub & Sharp 1996) and PC12 cells (Oda et al. 1997), higher Wm concentrations were found to inhibit secretion, and, where kinetic analysis was performed, Wm selectively eliminated the sustained phase of secretion without affecting its early rapid phase (Rao et al. 1997). These effects of Wm (which were often attributed to MLCK inhibition by early studies) probably result from inhibition of type III PI4K enzymes that are also targets of Wm at the same high concentration range. Wm therefore appears to affect the process of replenishment of the readily releasable pool, at least in some cells. Moreover, a phenylarsine-oxide (PAO)-sensitive PI4K was identified as necessary for secretion in chromaffin cells (Wiedemann et al. 1996) and in pancreatic β-cells (Olsen et al. 2003). While PAO can have several targets other than PI4Ks, among the latter, PI4 KIIIα (another Wm-sensitive PI4K) shows the highest sensitivity to PAO (Balla et al. 2002). Recent evidence suggests that the small Ca2+-binding protein, NCS-1, activates the Wm-sensitive PI4 KIIIβ enzyme and regulates priming and formation of the rapidly releasable vesicular pool in pancreatic β cells (Gromada et al. 2005). Similarly, reducing the levels of PI4 KIIIβ (Waselle et al. 2005) or PIP5KIγ (Gong et al. 2005, Waselle et al. 2005) has been shown to inhibit dense-core vesicle exocytosis. Recent studies have also indicated that PI3KC2α, by producing PtdIns(3)P, is also involved in neurosecretory granule exocytosis, adding 3-phosphorylated inositides to the list of potential regulators of the priming process (Meunier et al. 2005).

The regulatory role of phosphoinositides in synaptic vesicle release and recycling has also been well documented. Both synaptojanin-1, a phosphoinositide 5-phosphatase (McPherson et al. 1996), and PIP5KIγ (Wenk et al. 2001) have been shown to associate with synaptic vesicles, and knockout studies have confirmed that these enzymes are essential for normal synaptic functions, and have a role at multiple steps in synaptic vesicle exocytosis and recycling (Cremona et al. 1999, Di Paolo et al. 2004). Of the PI 4-kinases, PI4KIIα was shown to associate with synaptic vesicles (Guo et al. 2003). On the other hand, the Drosophila homolog of NCS-1, originally named frequenin and described as a major determinant of synaptic development and plasticity (Pongs et al. 1993), is a major regulator of the PI4KIIIβ protein (Weisz et al. 2000), as well as its yeast homolog, Pik1p (Hendricks et al. 1999). This suggests that there is a link between PI4KIIIβ function and synaptic transmission. It would not be surprising if both type-II and type-III PI4Ks were found to be important enzymes at distinct steps in the complex process of synaptic vesicle exocytosis and recycling.

Regarding the role of phosphoinositides in exocytosis, two additional questions remain to be answered. The first is whether the phosphoinositides are required on the surface of the secretory vesicles or at the plasma membrane, or perhaps in both locations. Initial reports have indicated that PtdIns(4,5)P2 is needed on the surface of the vesicles where the presence of the enzymes has been demonstrated (Martin et al. 1997). However, studies using the PLCδ1PH-GFP fusion protein to image PtdIns(4,5)P2 distribution failed to detect this lipid on the vesicular surface (Holz et al. 2000), indicating instead a significant increase in PtdIns(4,5)P2 at the contact sites in the plasma membrane associated with the vesicle fusion process (Holz et al. 2000, Aoyagi et al. 2005). A recent report has established that plasma membrane PtdIns(4,5)P2 levels are a determinant of the size of the readily releasable pool in chromaffin cells (Milosevic et al. 2005). Nevertheless, these observations do not rule out additional function(s) of PtdIns(4,5)P2 at the surface of secretory vesicles. Another question relates to the identity of the molecules that are the targets of PtdIns(4,5)P2. CAPS-1 (Ca2+-sensitive activator protein of secretion) has been identified as a crucial factor in DCV exocytosis that acts between docking and fusion (Walent et al. 1992). This protein was shown to be a PtdIns(4,5)P2-binding protein (Loyet et al. 1998) whose recruitment to the plasma membrane depended on PtdIns(4,5)P2 levels (Grishanin et al. 2004). Interestingly, while CAPS-1 has a central PH domain and PH domains generally serve as lipid-binding modules (Lemmon & Ferguson 2000), the CAPS-1 PH domain is not the principal lipid-binding site of the molecule (Grishanin et al. 2004). Other proteins have also been suggested as targets of phosphoinositides in regulated secretion. These include the Ca2+-sensitive SNARE-regulator protein, synaptotagmin, which binds inositides with its C2B domain (Schiavo et al. 1996, Bai et al. 2004); the Mint proteins (Okamoto & Sudhof 1997); and Rabphilin (Chung et al. 1998). Synaptotagmins have key roles in the Ca2+-triggered fusion process (Tucker & Chapman 2002), and their phosphoinositide binding has other functions than vesicle priming, again enforcing the idea that phosphoinositides contribute to the regulation of the secretory process in multiple ways.

Cellular lipid homeostasis and phosphoinositides

Although maintenance of cellular lipid homeostasis is a well-recognized function of all eukaryotic cells, traditionally only some of its aspects are subjects of endocrine research. This is in spite of the fact that lipid metabolism at the level of the whole organism is a central topic of endocrinology. The role or roles of phosphoinositides in the regulation of lipid synthesis and transport are not widely recognized, but recent findings suggest that these processes are also under the control of phosphoinositides. Studies on PH domains that recognize specific inositol lipids have revealed that a special subgroup of PH domains can bind PtdIns(4)P with remarkable specificity (Dowler et al. 2000). Proteins whose PH domains belong to this subgroup are the oxysterol-binding protein (OSBP), the ceramide-transfer protein (CERT) (Hanada et al. 2003) and the FAPP1 and FAPP2 proteins (Godi et al. 2004). With the exception of the FAPP1 protein, which appears to be a truncated adapter protein, all of these are lipid-binding/transfer proteins. The functions of OSBPs and their related proteins (ORPs) are mostly unknown, but they contain a lipid-binding motif that binds oxysterols or other phospholipids and a PH domain for interaction with membrane phosphoinositides (Lehto & Olkkonen 2003, Olkkonen & Lehto 2004). Oxysterols are among the most potent regulators of the transcription of genes that contribute to cholesterol synthesis and transport (Brown & Goldstein 1974, Olkkonen & Lehto 2004). OSBP overexpression increases cholesterol biosynthesis in chinese hamster ovary (CHO) cells (Lagace et al. 1997), and depletion of cholesterol or addition of 25-OH cholesterol promotes the association of OSBP with the Golgi complex (Ridgway et al. 1992, Storey et al. 1998). Since cholesterol biosynthesis is largely controlled by the SREBP transcription factor, whose nuclear translocation depends on its proteolytic cleavage in the Golgi complex (Brown & Goldstein 1999), the regulation of SREBP vesicular transport from the ER to the Golgi complex is a crucial step in cholesterol homeostasis and one that is likely to be controlled by PI 4-kinase(s). However, little is known about the connection between OSBP proteins and cholesterol homeostasis, and the involvement of phosphoinositides in SREBP trafficking.

More is known about the recently identified CERT protein, which is essential for the transport of ceramide from the site of its synthesis in the ER to the Golgi, where its conversion to sphingomyelin takes place (Perry & Ridgway 2005). CERT also contains a PH domain that binds PtdIns(4)P, and a single-point mutation within the PH domain that eliminates PtdIns(4)P binding is sufficient to render CERT completely dysfunctional (Hanada et al. 2003). PtdIns(4)P, therefore, is emerging as an important lipid regulator of the synthesis of sphingomyelin via its participation in the control of ceramide transport between the ER and the Golgi. It is a fascinating question why sufficient amounts of ceramide cannot reach the Golgi via the highly dynamic vesicular transport process that exists between the two organelles. This also suggests that ceramide is excluded from the budding CopII vesicles destined for the Golgi, probably because it is bound to a yet unidentified ER protein. The FAPP2 protein also contains a putative glycolipid-binding domain, but its natural ligand-binding partner is not known. The role (if any) that FAPP2 plays in cellular lipid metabolism, and whether the effects of FAPP2 knockdown on trafficking are related to its lipid-transport function, are also not known (Godi et al. 2004, Vieira et al. 2005).

Another indication of the importance of PtdIns(4)P in phospholipid synthesis comes from yeast studies. Synthesis of the aminophospholipid, phosphatidyl-ethanolamine (PE), via decarboxylation of ER-derived phosphatidylserine (PS), takes place either in the mitochondria or in Golgi membranes (Voelker 2005). PS, therefore, has to be transferred to those membranes in order to be decarboxylated, and genetic studies have shown that Stt4p (the yeast homolog of PI4KIII alpha) is a regulatory component of this process at the ER/Golgi (but not at the mitochondrial) site (Trotter et al. 1998). It is not yet known why the Stt4p kinase is needed for lipid transfer or whether it acts at the donor or acceptor membrane site. It also remains to be seen whether a similar regulation of aminophospholipid synthesis by PI 4-kinases or by other phosphoinositides is present in higher organisms.

Sec14p, the yeast PI/PC-TP, is as an essential component of the secretion process from the Golgi in Saccharomyces cerevisiae, and also functions in phosphatidylcholine (PC) metabolism and maintains DAG levels in the Golgi (Routt & Bankaitis 2004). There is an intimate relationship between Sec14p and PtdIns(4)P levels within the Golgi, since inactivation of the Sac1p inositol lipid phosphatase (Guo et al. 1999) can ‘bypass’ Sec14p defects (Whitters et al. 1993). Mammalian PITP proteins come in various forms: in addition to PITPα and -β, a highly homologous PITP module is found in some of the larger RdgB proteins that are homologs of the Drosophila retinal degeneration protein (Vihtelic et al. 1993). Two of the PITPs, the small PITPβ and large RdgBα1, are Golgi-localized proteins, and the latter was recently shown to be critical for Golgi morphology and function by controlling DAG levels (Litvak et al. 2005). In this regard, the lack of RdgBα1 in mammalian cells causes a defect similar to that seen in the yeast SEC14. The small PITPβ appears to be an essential gene in the mouse, but PITPα knockout mice are viable with prominent defects in the transport of re-esterified triglycerides from the ER in enterocytes and a similarly defective lipid handling of hepatocytes (Bankaitis et al. 2004). Reduced levels of PITPα are responsible for the early-onset neurodegeneration described in the vibrator mouse (Hamilton et al. 1997). PITPs are clearly an exciting group of proteins on the border of phospholipid metabolism and vesicular trafficking, and will surely surprise us with novel functions in the near future.

Nuclear receptors, nuclear signaling and inositol phospholipids

Steroid and thyroid hormones that bind to intracellular receptors and regulate the transcription of their target genes in the nucleus seem to defy the developments of phosphoinositide research. Although a fraction of almost all of the inositide kinases and PLCs have been shown to be present in the nucleus under certain conditions (Payrastre et al. 1992, Manzoli et al. 2005), and a separate nuclear phosphoinositide system has long been postulated (Irvine 2003), the link between the latter and the transcriptional apparatus has not been forthcoming. This gap began to narrow when genetic studies in yeast revealed that two inositol polyphosphate (IP) kinases, Ipk1 and Ipk2, are involved in mRNA export, chromatin remodeling and DNA metabolism (Odom et al. 2000, Shears 2004). These enzymes are critically important for the synthesis of highly phosphorylated inositols, such as InsP5 and InsP6, and also for the production of the pyrophosphorylated PP-InsP4 and PP-IP5, but it is not known at this point which (if any) of the highly phosphorylated inositols serves as an active regulatory species. Recent studies showed that the inositol pyrophosphates also regulate telomere length (Saiardi et al. 2005, York et al. 2005). Most recently, inositol multikinase, the mammalian homolog of Ipk2, was found to function as a wortmannin-insensitive PI 3-kinase in the nucleus. This observation raises the question of whether the lipids or the soluble inositol phosphates are the most important regulatory products of the enzyme (Carroll et al. 2004). In a separate line of research, structural characterization of the transcription factor, TFIIH, unveiled the presence of a PH domain in the molecule (Gervais et al. 2004). Moreover, an inositide-binding PHD domain was described in the chromatin-associated protein, ING2 (Gozani et al. 2003). The transcription factor Tubby, which, when mutated in mice, causes obesity, insulin resistance and sensory deficits (Carroll et al. 2004), was also shown to interact within its carboxy-terminal domain with plasma membrane PtdIns(4,5)P2. Only upon hydrolysis of the lipid does Tubby become free to translocate to the nucleus (Santagata et al. 2001). The recent discovery of nuclear orphan receptors that bind phospholipids (Li et al. 2005), including PtdIns(3,4,5)P3, as ligands (Krylova et al. 2005) is the latest addition to a list of nuclear proteins potentially regulated by phosphoinositides. It is expected that this area of research will greatly expand in the near future, putting nuclear events on a par with membrane-associated signaling processes as regulatory targets of phosphoinositides.

Concluding remarks

These examples of inositol lipid-regulated processes contributing to the complex cellular responses to hormones and neurotransmitters represent only a limited selection from the multitude of actions of phosphoinositides. The purpose of discussing them in this context was to identify areas of interest and to facilitate the incorporation of phosphoinositides as important topics in endocrine research. Over the last decade, it has become increasingly clear that the molecular elements of the classical messenger cascades, such as receptors, G proteins, ion channels and ‘effectors’, such as PLCs and A- or G- cyclases, are actively organized within the cell in the relevant membrane compartments. Phosphoinositides are at least as important in the trafficking and organization of signaling complexes as they are in the rapid generation of intracellular messengers. It is not too difficult to foresee a great expansion of knowledge in this research area and that cellular endocrinology will be an active contributor to, as well as a beneficiary of, this expansion.

Figure 1
Figure 1

Updated version of the classical ‘PI cycle’. Plasma membrane PtdIns(4,5)P2 is hydrolyzed by PLC enzymes, after receptor stimulation, to generate two second messengers, Ins(1,4,5)P3 and DAG. Ins(1,4,5)P3, which mobilizes intracellular Ca2+, is rapidly degraded by sequential dephosphorylations to yield myo-inositol. (A fraction of the Ins(1,4,5)P3 is converted to higher inositol phosphates via pathways that differ between plants, yeast and vertebrates (Shears 2004), but it is not shown in the figure for better clarity.) Some of the dephosphorylating enzymes on the pathway of Ins(1,4,5)P3 degradation are sensitive to inhibition by Li+ ions, a finding that led to the idea that the therapeutic effects of Li+ in bipolar disorder might be related to altered signaling affecting primarily hyperactive receptors (Berridge et al. 1989). DAG, the other product of PtdnIns(4,5)P2 hydrolysis, activates PKC enzymes (and some other effectors, such as ion channels or protein kinase D (PKD) – not shown) before being converted to PtdA by DAG-kinase enzymes. PtdA of the plasma membrane can also activate certain effectors (not shown). In the endoplasmic reticulum (ER), PtdA is converted to CDP-DAG, which is conjugated with myo-inositol by PI synthase enzyme(s). When cells are stimulated in the presence of Li+, CDP-DAG accumulates because of the shortage of myo-inositol derived from phosphoinositide hydrolysis. The PtdIns of the ER is transferred to the plasma membrane by PI transfer proteins, but it is less clear whether a similar mechanism transfers PtdA between the membranes. Most downstream pathways in this messenger system are regulated by PKC and other Ca2+-responsive protein kinases or phosphatases.

Citation: Journal of Endocrinology 188, 2; 10.1677/joe.1.06595

Figure 2
Figure 2

G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) activate PtdIns(4,5)P2 hydrolysis by distinct mechanisms, the former using G protein-mediated activation of PLCβ isoforms, and the latter causing PLCγ activation. Ins(1,4,5)P3 binds to its receptors located primarily in the ER in the form of tetrameric Ca2+ channels releasing Ca2+ from the internal stores. The N-terminal Ins(1,4,5)P3-binding domain of the InsP3 receptor is probably in close proximity to the C-terminal channel domain with a long intervening regulatory domain (see insert). Emptying of the ER Ca2+ pools relays information (by unknown mechanisms) to plasma membrane Ca2+ channels, commonly termed store-operated Ca2+ channels (SOC), to enhance Ca2+ influx into the cell. Members of the TRP family of Ca2+ channels may function as SOC, and it has been suggested that there is a physical regulatory contact between plasma membrane-adjacent InsP3 receptors and certain TRP channels (see text for details). Another spatial organization is related to the ‘coupling’ of Ca2+ release via the InsP3 receptors with uptake by mitochondria that are juxtaposed to InsP3 receptor-rich ER domains.

Citation: Journal of Endocrinology 188, 2; 10.1677/joe.1.06595

Figure 3
Figure 3

The network of interconversions between phosphoinositides. Phosphoinositides are phosphorylated (red arrows) by inositide kinases and are dephosphorylated (blue arrows) by phosphoinositide phosphatases. Most (but not all) of the kinases are quite specific and phosphorylate only one substrate in a specific position on the inositol ring. Some kinases (such as the class II PI 3-kinases, PI3KC2) show wider substrate tolerance in vitro but are likely to have a clear substrate preference in vivo. The substrate specificity of most (but not all) phosphatases is less stringent in vitro, and some can dephosphorylate lipids as well as the soluble inositol phosphates. The physiologic and preferred substrate is not known for all inositide phosphatases, nor is it known in all cases which enzyme or enzymes are primarily responsible for a specific interconversion step. For example, Sac1 phosphatases can remove the 3- and 4-phosphates from a mono-phosphorylated inositol lipid, but synaptojanins (Snj), which are primarily known as 5-phosphatases, also contain a Sac1 phosphatase motif and can function as Sac1 phosphatases (Guo et al. 1999). Since myotubularin-related inositol lipid phosphatases (MTMRs) (Taylor & Dixon 2003) also dephosphorylate the 3 position on PtdIns(3)P, it is likely that PtdIns(3)P is dephosphorylated by Sac1, Snj-s and MTMRs in different cellular compartments (Parrish et al. 2004). This figure indicates only the more established routes; for all other possibilities of interconversion, see Abel et al.(2001).

Citation: Journal of Endocrinology 188, 2; 10.1677/joe.1.06595

Figure 4
Figure 4

The general scheme of endocytosis from the plasma membrane. Transmembrane proteins (e.g. receptors) associate with adapter proteins capable of recognizing the internalization signal (usually within their membrane-adjacent cytoplasmic sequence). (Often, a covalent modification, such as phosphorylation or ubiquitination, takes place at these sites on the transmembrane proteins – not shown here.) The adapter protein interaction is also aided by the presence of membrane phosphoinositides and requires an active small GTP-binding protein (such as Arfs or Rabs). The adapter protein also binds clathrin, thereby recruiting the protein into clathrin-coated pits. Several adapter proteins have been shown to bind phosphoinositides, which, in most cases, are the most abundant PtdIns(4,5)P2. Once the vesicles are pinched off (clathrin-coated vesicles, CV), this lipid is no longer demonstrable in the vesicles and is replaced by 3-phosphorylated inositides, contributing to a new identity of the vesicles. Recent studies also indicate that PtdIns(3,4,5)P3 formed in the membrane can be a source of 3-phosphorylated lipids in the endosomes after sequential dephosphorylations by vesicle-associated phosphatases that remove the 5- and 4- phosphates (Ivetac et al. 2005, Shin et al. 2005). Multivesicular bodies are formed from early endosomes (EE) after inward invagination and budding, and PtdIns(3,5)P2 is a critical component of this process (see text for more details).

Citation: Journal of Endocrinology 188, 2; 10.1677/joe.1.06595

Figure 5
Figure 5

Multiple steps in the exocytic process. Secretory vesicles containing their cargo become docked to the plasma membrane to form the rapidly releasable vesicular pool by maturation. During maturation, which is an ATP-dependent process, these vesicles become ‘primed’, that is, ready for release once the Ca2+-induced triggering takes place. Synthesis of phosphoinositides (probably PtdIns(4,5)P2) is part of the priming process, and the recruitment of the Ca2+-binding regulatory protein CAPS (which also binds PtdIns(4,5)P2) is an essential component of priming. Vesicles are stabilized by the t- and v-snare proteins (syntaxin and VAMP respectively), and they respond to Ca2+ increases via synaptotagmin (a protein also capable of phosphoinositide binding), which ultimately triggers the conformational change(s) leading to pore opening and cargo release. Phosphoinositides as well as Ca2+ increases act at multiple steps, and production of the lipid both at the membrane and on the surface of the vesicles may take place.

Citation: Journal of Endocrinology 188, 2; 10.1677/joe.1.06595

I thank Dr Kevin J Catt (NICHD, NIH) for his critical reading of the manuscript and helpful suggestions. This research is supported by the Intramural Research Program of the National Institute of Child Health and Human Development of the National Institutes of Health. The author declares that there is no conflict of interest that would prejudice the impartiality of this scientific work.

References

  • AbelK Anderson RA & Shears SB 2001 Phosphatidylinositol and inositol phosphate metabolism. Journal of Cell Science1142207–2208.

  • AlessiDR James SR Downes CP Holmes AB Gaffney PR Reese CB & Cohen P 1997 Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current Biology7261–269.

    • Search Google Scholar
    • Export Citation
  • AoyagiK Sugaya T Umeda M Yamamoto S Terakawa S & Takahashi M 2005 The activation of exocytotic sites by the formation of phosphatidylinositol 45-bisphosphate microdomains at syntaxin clusters. Journal of Biological Chemistry28017346–17352.

    • Search Google Scholar
    • Export Citation
  • BaiJ Tucker WC & Chapman ER 2004 PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nature Structural and Molecular Biology1136–44.

    • Search Google Scholar
    • Export Citation
  • BallaT1998 Phosphatidylinositol 4-kinases. Biochimica Biophysica Acta143669–85.

  • BallaA Tuymetova G Barshishat M Geiszt M & Balla T 2002 Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments. Journal of Biological Chemistry27720041–22050.

    • Search Google Scholar
    • Export Citation
  • BallaA Tuymetova G Tsiomenko A Varnai P & Balla T 2005 A plasma membrane pool of phosphatidylinositol 4-phosphate is generated by phosphatidylinositol 4-kinase type-III alpha: studies with the PH domains of the oxysterol binding protein and FAPP1. Molecular Biology of the Cell161282–1295.

    • Search Google Scholar
    • Export Citation
  • BankaitisVA Cortese J Phillips SE & Alb JG Jr 2004 Phosphatidylinositol transfer protein function in the mouse. Advances in Enzyme Regulation44201–218.

    • Search Google Scholar
    • Export Citation
  • BarylkoB Gerber SH Binns DD Grichine N Khvotchev M Sudhof TC & Albanesi JP 2001 A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans. Journal of Biological Chemistry2767705–7708.

    • Search Google Scholar
    • Export Citation
  • BerridgeMJ1984 Inositol trisphosphate and diacylglycerol as intracellular messengers. Biochemical Journal220345–360.

  • BerridgeMJ Downes CP & Hanley MR 1989 Neural and developmental actions of lithium: a unifying hypothesis. Cell59411–419.

  • BezprozvannyI Watras J & Ehrlich BE 1991 Bell-shaped calcium-response curves of Ins(145)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature351751–754.

    • Search Google Scholar
    • Export Citation
  • BezzeridesVJ Ramsey IS Kotecha S Greka A & Clapham DE 2004 Rapid vesicular translocation and insertion of TRP channels. Nature Cell Biology6709–720.

    • Search Google Scholar
    • Export Citation
  • BiL Okabe I Bernard DJ Wynshaw-Boris A & Nussbaum RL 1999 Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110 alpha subunit of phosphoinositide 3-kinase. Journal of Biological Chemistry27410963–10968.

    • Search Google Scholar
    • Export Citation
  • BiL Okabe I Bernard DJ & Nussbaum RL 2002 Early embryonic lethality in mice deficient in the p110 beta catalytic subunit of PI 3-kinase. Mammalian Genome13169–172.

    • Search Google Scholar
    • Export Citation
  • BoehningD & Joseph SK 2000 Direct association of ligand-binding and pore domains in homo- and heterotetrameric inositol 145-trisphosphate receptors. EMBO Journal195450–5459.

    • Search Google Scholar
    • Export Citation
  • BonifacinoJS & Weissman AM 1998 Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annual Review of Cell and Developmental Biology1419–57.

    • Search Google Scholar
    • Export Citation
  • BonifacinoJS & Traub LM 2003 Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annual Review of Biochemistry72395–447.

    • Search Google Scholar
    • Export Citation
  • BosanacI Alattia JR Mal TK Chan J Talarico S Tong FK Tong KI Yoshikawa F Furiuchi T Iwai M et al.2002 Structure of the inositol 145-trishphosphate receptor binding core in complex with its ligand. Nature420696–700.

    • Search Google Scholar
    • Export Citation
  • BosanacI Yamazaki H Matsu-ura T Michikawa T Mikoshiba K & Ikura M 2005 Crystal structure of the ligand binding suppressor domain of type 1 inositol 145-trisphosphate receptor. Molecular Cell17193–203.

    • Search Google Scholar
    • Export Citation
  • BrownMS & Goldstein JL 1974 Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. Journal of Biological Chemistry2497306–7314.

    • Search Google Scholar
    • Export Citation
  • BrownMS & Goldstein JL 1979 Receptor-mediated endocytosis: insights from the lipoprotein receptor system. PNAS763330–3337.

  • BrownMS & Goldstein JL 1999 A proteolytic pathway that controls the cholesterol content of membranes cells and blood. PNAS9611041–11048.

    • Search Google Scholar
    • Export Citation
  • CarmanCV Barak LS Chen C Liu-Chen L-Y Onorato JJ Kennedy SP Caron MG & Benovic JL 2000 Mutational analysis of Gβγ and phospholipid interaction with G protein-coupled receptor kinase 2. Journal of Biological Chemistry27510443–10452.

    • Search Google Scholar
    • Export Citation
  • CarrollK Gomez C & Shapiro L 2004 Tubby proteins: the plot thickens. Nature Reviews. Molecular Cell Biology555–63.

  • CheminJ Patel AJ Duprat F Lauritzen I Lazdunski M & Honore E 2005 A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO Journal2444–53.

    • Search Google Scholar
    • Export Citation
  • ChongLD Traynor-Kaplan A Bokoch GM & Schwartz MA 1994 The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell79507–513.

    • Search Google Scholar
    • Export Citation
  • ChuangHH Prescott ED Kong H Shields S Jordt SE Basbaum AI Chao MV & Julius D 2001 Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(45)P2-mediated inhibition. Nature411957–962.

    • Search Google Scholar
    • Export Citation
  • ChungSH Song WJ Kim K Bednarski JJ Chen J Prestwich GD & Holz RW 1998 The C2 domains of Rabphilin3A specifically bind phosphatidylinositol 45-bisphosphate containing vesicles in a Ca2+-dependent manner. In vitro characteristics and possible significance. Journal of Biological Chemistry27310240–10248.

    • Search Google Scholar
    • Export Citation
  • CockcroftS1981 Does phosphatidylinositol breakdown control the Ca2+-gating mechanism? Trends in Pharmacological Sciences2340–342.

  • CremonaO Di Paolo G Wenk MR Luthi A Kim WT Takei K Daniell L Nemoto Y Shears SB Flavell RA et al.1999 Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell99179–188.

    • Search Google Scholar
    • Export Citation
  • CsordasG Thomas AP & Hajnoczky G 1999 Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO Journal1896–108.

    • Search Google Scholar
    • Export Citation
  • da FonsecaPC Morris SA Nerou EP Taylor CW & Morris EP 2003 Domain organization of the type 1 inositol 145-trisphosphate receptor as revealed by single-particle analysis. PNAS1003936–3941.

    • Search Google Scholar
    • Export Citation
  • DaleLB Seachrist JL Babwah AV & Ferguson SS 2004 Regulation of angiotensin II type 1A receptor intracellular retention degradation and recycling by Rab5 Rab7 and Rab11 GTPases. Journal of Biological Chemistry27913110–13118.

    • Search Google Scholar
    • Export Citation
  • DaubH Weiss FU Wallasch C & Ullrich A 1996 Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature379557–560.

    • Search Google Scholar
    • Export Citation
  • DawsonAP & Irvine RF 1984 Inositol(145)trisphosphate-promoted Ca2+ release from microsomal fractions of rat liver. Biochemical Biophysical Research Communications120858–864.

    • Search Google Scholar
    • Export Citation
  • DikicI2003 Mechanisms controlling EGF receptor endocytosis and degradation. Biochemical Society Transactions311178–1181.

  • Di PaoloG Moskowitz HS Gipson K Wenk MR Voronov S Obayashi M Flavell R Fitzsimonds RM Ryan TA & De Camilli P 2004 Impaired PtdIns(45)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature431415–422.

    • Search Google Scholar
    • Export Citation
  • DowlerS Currie RA Campbell DG Deak M Kular G Downes CP & Alessi DR 2000 Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochemical Journal35119–31.

    • Search Google Scholar
    • Export Citation
  • EberhardDA Cooper CL Low MG & Holz RW 1990 Evidence that the inositol phospholipids are necessary for exocytosis. Biochemical Journal26815–25.

    • Search Google Scholar
    • Export Citation
  • FrankeTF Kaplan DR Cantley LC & Toker A 1997 Direct regulation of the Akt protooncogene product by PI(34)P2. Science275665–668.

  • FrumanDA Meyers RE & Cantley LC 1998 Phosphoinositide kinases. Annual Review of Biochemistry67481–507.

  • FrumanDA Mauvais-Jarvis F Pollard DA Yballe CM Brazil D Bronson RT Kahn CR & Cantley LC 2000 Hypoglycaemia liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nature Genetics26379–382.

    • Search Google Scholar
    • Export Citation
  • FuruichiT Yoshikawa S Miyawaki A Wada K Maeda N & Mikoshiba K 1989 Primary structure and functional expression of the inositol 145-trisphosphate-binding protein P400. Nature34232–38.

    • Search Google Scholar
    • Export Citation
  • GaborikZ & Hunyady L 2004 Intracellular trafficking of hormone receptors. Trends in Endocrinology and Metabolism15286–293.

  • GaidarovI Krupnick JG Falck JR Benovic JL & Keen JH 1999 Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. EMBO Journal18871–881.

    • Search Google Scholar
    • Export Citation
  • GalvanDL Borrego-Diaz E Perez PJ & Mignery GA 1999 Subunit oligomerization and topology of the inositol 145-trisphosphate receptor. Journal of Biological Chemistry27429483–29492.

    • Search Google Scholar
    • Export Citation
  • GervaisV Lamour V Jawhari A Frindel F Wasielewski E Dubaele S Egly J-M Thierry J-C Kieffer B & Poterszman A 2004 TFIIH contains a PH domain involved in DNA nucleotide excision repair. Nature Structural and Molecular Biology11616–622.

    • Search Google Scholar
    • Export Citation
  • GlouchankovaL Krishna UM Potter BV Falck JR & Bezprozvanny I 2000 Association of the inositol (145)-trisphosphate receptor ligand binding site with phosphatidylinositol (45)-bisphosphate and adenophostin A. Molecular Cell Biology Research Communication3153–158.

    • Search Google Scholar
    • Export Citation
  • GodiA Di Campi A Konstantakopoulos A Di Tullio G Alessi DR Kular GS Daniele T Marra P Lucocq JM & De Matteis MA 2004 FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P. Nature Cell Biology6393–404.

    • Search Google Scholar
    • Export Citation
  • GongLW Di Paolo G Diaz E Cestra G Diaz ME Lindau M De Camilli P & Toomre D 2005 Phosphatidylinositol phosphate kinase type I gamma regulates dynamics of large dense-core vesicle fusion. PNAS1025204–5209.

    • Search Google Scholar
    • Export Citation
  • GozaniO Karuman P Jones DR Ivanov D Cha J Logovskoy AA Baird CL Zhu H Field SJ Lessnick SL et al.2003 The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell11499–111.

    • Search Google Scholar
    • Export Citation
  • GrishaninRN Kowalchyk JA Klenchin VA Ann K Earles CA Chapman ER Gerona RR & Martin TF 2004 CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein. Neuron43551–562.

    • Search Google Scholar
    • Export Citation
  • GromadaJ Bark C Smidt K Efanov AM Janson J Mandic SA Webb DL Zhang W Meister B Jeromin A et al.2005 Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta. PNAS10210303–10308.

    • Search Google Scholar
    • Export Citation
  • GuillemetteG Balla T Baukal AJ & Catt KJ 1988 Characterization of inositol 145-trisphosphate receptors and calcium mobilization in a hepatic plasma membrane fraction. Journal of Biological Chemistry2634541–4548.

    • Search Google Scholar
    • Export Citation
  • GuoJ Wenk MR Pellegrini L Onofri F Benfenati F & De Camilli P 2003 Phosphatidylinositol 4-kinase type IIalpha is responsible for the phosphatidylinositol 4-kinase activity associated with synaptic vesicles. PNAS1003995–4000.

    • Search Google Scholar
    • Export Citation
  • GuoS Stolz LE Lemrow SM & York JD 1999 SAC1-like domains of yeast SAC1 INP52 and INP53 and of human synaptojanin encode polyphosphoinositide phosphatases. Journal of Biological Chemistry27412990–12995.

    • Search Google Scholar
    • Export Citation
  • HaglundK Di Fiore PP & Dikic I 2003 Distinct monoubiquitin signals in receptor endocytosis. Trends in Biochemical Sciences28598–603.

  • HajnoczkyG & Thomas AP 1994 The inositol trisphosphate calcium channel is inactivated by inositol trisphosphate. Nature370474–477.

  • HajnoczkyG Robb-Gaspers LD Seitz MB & Thomas AP 1995 Decoding of cytosolic calcium oscillations in the mitochondria. Cell82415–424.

  • HamiltonBA Smith DJ Mueller KL Kerrebrock AW Bronson RT van Berkel V Daly MJ Kruglyak L Reeve MP Nemhauser JL et al.1997 The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression. Neuron18711–722.

    • Search Google Scholar
    • Export Citation
  • HanadaK Kumagai K Yasuda S Miura Y Kawano M Fukasawa M & Nishijima M 2003 Molecular machinery for non-vesicular trafficking of ceramide. Nature426803–809.

    • Search Google Scholar
    • Export Citation
  • HardieRC2003 Regulation of TRP channels via lipid second messengers. Annual Review of Physiology65735–759.

  • HayJC & Martin TFJ 1993 Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca2+-activated secretion. Nature366572–575.

    • Search Google Scholar
    • Export Citation
  • HayJC Fisette PL Jenkins GH Fukami K Takenawa T Anderson RA & Martin TFJ 1995 ATP-dependent inositide phosphorylation required for Ca2+-activated secretion. Nature374173–177.

    • Search Google Scholar
    • Export Citation
  • HendricksKB Wang BQ Schnieders EA & Thorner J 1999 Yeast homologue of neuronal frequenin is a regulator of phosphatidylinositol 4-OH-kinase. Nature Cell Biology1234–241.

    • Search Google Scholar
    • Export Citation
  • HickeL2001 A new ticket for entry into budding vesicles –ubiquitin. Cell106527–530.

  • HilgemannDW & Ball R 1996 Regulation of cardiac Na+ Ca2+ exchange and KATP potassium channels by PIP2. Science273956–959.

  • HinchliffeAK Ciruela A & Irvine RF 1998 PIPkins their substrates and their products: new functions for old enzymes. Biochimica Biophysica Acta143687–104.

    • Search Google Scholar
    • Export Citation
  • HolzRW Hlubek MD Sorensen SD Fisher SK Balla T Ozaki S Prestwich GD Stuenkel EL & Bittner MA 2000 A pleckstrin homology domain specific for Ptdins-45-P2 and fused to green fluorescent protein identifies plasma membrane Ptdins-45-P2 as being important in exocytosis. Journal of Biological Chemistry27517878–17885.

    • Search Google Scholar
    • Export Citation
  • HondaA Nogami M Yokozeki T Yamazaki M Nakamura H Watanabe H Kawamoto K Nakayama K Morris AJ Frohman MA et al.1999 Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell99521–532.

    • Search Google Scholar
    • Export Citation
  • HorowitzLF Hirdes W Suh BC Hilgemann DW Mackie K & Hille B 2005 Phospholipase C in living cells: activation inhibition Ca2+ requirement and regulation of M current. Journal of General Physiology126243–262.

    • Search Google Scholar
    • Export Citation
  • HothM & Penner R 1992 Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature355353–356.

  • HuangCL Feng S & Hilgemann DW 1998 Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature391803–806.

    • Search Google Scholar
    • Export Citation
  • HunyadyL Baukal AJ Gaborik Z Olivares-Reyes JA Bor M Szaszak M Lodge R Catt KJ & Balla T 2002 Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT1 angiotensin receptor. Journal of Cell Biology1571211–1222.

    • Search Google Scholar
    • Export Citation
  • IrvineRF2003 Nuclear lipid signalling. Nature Reviews. Molecular Cell Biology4349–360.

  • IvetacI Munday AD Kisseleva MV Zhang XM Luff S Tiganis T Whisstock JC Rowe T Majerus PW & Mitchell CA 2005 The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane. Molecular Biology of the Cell162218–2233.

    • Search Google Scholar
    • Export Citation
  • JiangQ-X Thrower EC Chester DW Ehrlich BE & Sigworth FJ 2002 Three-dimensional structure of the type 1 inositol 145-trisphosphate receptor at 24 A resolution. EMBO Journal213575–3581.

    • Search Google Scholar
    • Export Citation
  • JolyM Kazlauskas A Fay FS & Corvera S 1994 Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science263684–687.

    • Search Google Scholar
    • Export Citation
  • KatzmannDJ Odorozzi G & Emr SD 2002 Receptor downregulation and multivesicular-body sorting. Nature Reviews. Molecular Cell Biology3893–905.

    • Search Google Scholar
    • Export Citation
  • KiselyovK Xu X Mozhayeva G Kuo T Pessah I Migniery G Zhu X Birnbaumer L & Muallem S 1998 Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature396478–482.

    • Search Google Scholar
    • Export Citation
  • KorehK & Monaco ME 1986 The relationship of hormone-sensitive and hormone-insensitive phosphatidylinositol to phosphatidylinositol 45-bisphosphate in the WRK-1 cell. Journal of Biological Chemistry26188–91.

    • Search Google Scholar
    • Export Citation
  • KrapivinskyG Gordon EA Wickman K Velimirovic B Krapivinsky L & Clapham DE 1995 The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature374135–141.

    • Search Google Scholar
    • Export Citation
  • KrylovaIN Sablin EP Moore J Xu RX Waitt GM MacKay JA Juzumiene D Bynum JM Madauss K Montana V et al.2005 Structural analyses reveal phosphatidylinositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell120343–355.

    • Search Google Scholar
    • Export Citation
  • LagaceTA Byers DM Cook HW & Ridgway ND 1997 Altered regulation of cholesterol and cholesteryl ester synthesis in Chinese-hamster ovary cells overexpressing the oxysterol-binding protein is dependent on the pleckstrin homology domain. Biochemical Journal326205–213.

    • Search Google Scholar
    • Export Citation
  • LeeA Frank DW Marks MS & Lemmon MA 1999 Dominant-negative inhibition of receptor-mediated endocytosis by a dynamin-1 mutant with a defective pleckstrin homology domain. Current Biology9261–264.

    • Search Google Scholar
    • Export Citation
  • LeeS-J Xu H Kang L-W Amzel LM & Montell C 2003 Light adaptation through phosphoinositide-regulated translocation of Drosophila visual arrestin. Neuron39121–132.

    • Search Google Scholar
    • Export Citation
  • LefkowitzRJ1993 G protein-coupled receptor kinases. Cell74409–412.

  • LehtoM & Olkkonen VM 2003 The OSBP-related proteins: a novel protein family involved in vesicle transport cellular lipid metabolism and cell signalling. Biochimica Biophysica Acta16311–11.

    • Search Google Scholar
    • Export Citation
  • LemmonMA & Ferguson KM 2000 Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochemical Journal3501–18.

  • LeopoldtD Hanck T Exner T Maier U Wetzker R & Nurnberg B 1998 Gβγ stimulates phosphoinositide 3-kinase-gamma by direct interaction with two domains of the catalytic p110 subunit. Journal of Biological Chemistry2737024–7029.

    • Search Google Scholar
    • Export Citation
  • LiY Choi M Cavey G Daugherty J Suino K Kovach A Bingham NC Kliewer SA & Xu EH 2005 Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Molecular Cell17491–502.

    • Search Google Scholar
    • Export Citation
  • LintschingerB Balzer-Geldsetzer M Baskaran T Graier WF Romanin C Zhu MX & Groschner K 2000 Coassembly of Trp1 and Trp3 proteins generates diacylglycerol- and Ca2+-sensitive cation channels. Journal of Biological Chemistry27527799–27805.

    • Search Google Scholar
    • Export Citation
  • LiouJ Kim ML Heo WD Jones JT Myers JW Ferrell JE Jr & Meyer T 2005 STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Current Biology151235–1241.

    • Search Google Scholar
    • Export Citation
  • LitvakV Dahan N Ramachandran S Sabanay H & Lev S 2005 Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function. Nature Cell Biology7225–234.

    • Search Google Scholar
    • Export Citation
  • LiuB Zhang C & Qin F 2005 Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 45-bisphosphate. Journal of Neuroscience254835–4843.

    • Search Google Scholar
    • Export Citation
  • LiuX Singh BB & Ambudkar IS 2003 TRPC1 is required for functional store-operated Ca2+ channels. Role of acidic amino acid residues in the S5–S6 region. Journal of Biological Chemistry27811337–11343.

    • Search Google Scholar
    • Export Citation
  • LopesCM Rohacs T Czirjak G Balla T Enyedi P & Logothetis DE 2005 PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels. Journal of Physiology (Lond)564117–129.

    • Search Google Scholar
    • Export Citation
  • LoyetKM Kowalchyk JA Chaudhary A Chen J Prestwitch GD & Martin TF 1998 Specific binding of phosphatidylinositol 45-bisphosphate to calcium-dependent activator protein for secretion (CAPS) a potential phosphoinositide effector protein for regulated exocytosis. Journal of Biological Chemistry2738337–8343.

    • Search Google Scholar
    • Export Citation
  • LuoJ Field SJ Lee JY Engelman JA & Cantley LC 2005 The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. Journal of Cell Biology170455–464.

    • Search Google Scholar
    • Export Citation
  • LuttrellLM & Lefkowitz RJ 2002 The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. Journal of Cell Science115455–465.

    • Search Google Scholar
    • Export Citation
  • MaedaN Kawasaki T Nakade S Yokota N Taguchi T Kasai M & Mikoshiba K 1991 Structural and functional characterization of inositol 145-trisphosphate receptor channel from mouse cerebellum. Journal of Biological Chemistry2661109–1116.

    • Search Google Scholar
    • Export Citation
  • MajerusPW Kisseleva MV & Norris FA 1999 The role of phosphatases in inositol signaling reactions. Journal of Biological Chemistry27410669–10672.

    • Search Google Scholar
    • Export Citation
  • MakDO & Foskett JK 1994 Single-channel inositol 145-trisphosphate receptor currents revealed by patch clamp of isolated Xenopus oocyte nuclei. Journal of Biological Chemistry26929375–29378.

    • Search Google Scholar
    • Export Citation
  • ManzoliL Martelli AM Billi AM Faenza I Fiume R & Cocco L 2005 Nuclear phospholipase C: involvement in signal transduction. Progress in Lipid Research44185–206.

    • Search Google Scholar
    • Export Citation
  • MarcheseA & Benovic JL 2001 Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. Journal of Biological Chemistry27645509–45512.

    • Search Google Scholar
    • Export Citation
  • MartinTF2003 Tuning exocytosis for speed: fast and slow modes. Biochimica Biophysica Acta1641157–165.

  • MartinTFJ Loyet KM Barry VA & Kowalchik JA 1997 The role of PtdIns(45)P2 in exocytotic membrane fusion. Biochemical Society Transactions251137–1141.

    • Search Google Scholar
    • Export Citation
  • McPhersonPS Garcia EP Slepnev VI David C Zhang X Grabs D Sossin WS Bauerfeind R Nemoto Y & De Camilli P 1996 A presynaptic inositol-5-phosphatase. Nature379353–357.

    • Search Google Scholar
    • Export Citation
  • MeunierFA Osborne SL Hammond GR Cooke FT Parker PJ Domin J & Schiavo G 2005 Phosphatidylinositol 3-kinase C2α is essential for ATP-dependent priming of neurosecretory granule exocytosis. Molecular Biology of the Cell164841–4851.

    • Search Google Scholar
    • Export Citation
  • MichellRH1982 Is phosphatidylinositol really out of the calcium gate? Nature296492–493.

  • MigneryGA & Sudhof TC 1990 The ligand binding site and transduction mechanism in the inositol-145-triphosphate receptor. EMBO Journal93893–3898.

    • Search Google Scholar
    • Export Citation
  • MigneryGA Sudhof TC Takei K & De Camilli P 1989 Putative receptor for inositol 145-trisphosphate similar to ryanodine receptor. Nature342192–195.

    • Search Google Scholar
    • Export Citation
  • MikoshibaK1993 Inositol 145-trisphosphate receptor. Trends in Pharmacological Sciences1486–89.

  • MikoshibaK1997 The InsP3 receptor and intracellular signaling. Current Opinion in Neurobiology7339–345.

  • MilosevicI Sorensen JB Lang T Krauss M Nagy G Haucke V Jahn R & Neher E 2005 Plasmalemmal phosphatidylinositol-45-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells. Journal of Neuroscience252557–2565.

    • Search Google Scholar
    • Export Citation
  • MoraA Komander D Van Aalten DM & Alessi DR 2004 PDK1 the master regulator of AGC kinase signal transduction. Seminars in Cellular and Developmental Biology15161–170.

    • Search Google Scholar
    • Export Citation
  • MoriY Wakamori M Miyakawa T Hermosura M Hara Y Nishida M Hirose K Mizushima A Kurosaki M Mori E et al.2002 Transient receptor potential 1 regulates capacitative Ca2+ entry and Ca2+ release from endoplasmic reticulum in B lymphocytes. Journal of Experimental Medicine195673–681.

    • Search Google Scholar
    • Export Citation
  • Naga PrasadSV Laporte SA Chamberlain D Caron MG Barak L & Rockman HL 2002 Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. Journal of Cell Biology158563–575.

    • Search Google Scholar
    • Export Citation
  • Naga PrasadSV Jayatilleke A Madamanchi A & Rockman HA 2005 Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nature Cell Biology7785–796.

    • Search Google Scholar
    • Export Citation
  • NakanishiS Catt KJ & Balla T 1995 A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. PNAS925317–5321.

    • Search Google Scholar
    • Export Citation
  • NishizukaY1988 The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature34661–665.

  • OdaH Murayama T & Nomura Y 1997 Inhibition of protein kinase C-dependent noradrenaline release by wortmannin in PC12 cells. Archives in Biochemistry and Biophysics33796–102.

    • Search Google Scholar
    • Export Citation
  • OdomAR Stahlberg A Wente SR & York JD 2000 A role for nuclear inositol 145-trisphosphate kinase in transcriptional control. Science2872026–2029.

    • Search Google Scholar
    • Export Citation
  • OdorozziG Babst M & Emr SD 1998 Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body. Cell95847–858.

    • Search Google Scholar
    • Export Citation
  • OkamotoM & Sudhof TC 1997 Mints Munc18-interacting proteins in synaptic vesicle exocytosis. Journal of Biological Chemistry27231459–31464.

    • Search Google Scholar
    • Export Citation
  • OlkkonenVM & Lehto M 2004 Oxysterols and oxysterol binding proteins: role in lipid metabolism and atherosclerosis. Annals of Medicine36562–572.

    • Search Google Scholar
    • Export Citation
  • OlsenHL Hoy M Zhang W Bertorello AM Bokvist K Capito K Efanov AM Meister B Thams P Yang SN et al.2003 Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells. PNAS1005187–5192.

    • Search Google Scholar
    • Export Citation
  • OtsuM Hiles I Gout I Fry MJ Ruiz-Larrea F Panayotou G Thompson A Dhand R Hsuan JJ et al.1991 Characterization of two 85 kDa proteins that associate with receptor tyrosine kinases middle-T/pp60c-src complexes and PI3-kinase. Cell6591–104.

    • Search Google Scholar
    • Export Citation
  • OwenDJ Collins BM & Evans PR 2004 Adaptors for clathrin coats: structure and function. Annual Review of Cell and Developmental Biology20153–191.

    • Search Google Scholar
    • Export Citation
  • PacherP & Hajnoczky G 2001 Propagation of the apoptotic signal by mitochondrial waves. EMBO Journal204107–4121.

  • PadronD Wang YJ Yamamoto M Yin H & Roth MG 2003 Phosphatidylinositol phosphate 5-kinase Ibeta recruits AP-2 to the plasma membrane and regulates rates of constitutive endocytosis. Journal of Cell Biology162693–701.

    • Search Google Scholar
    • Export Citation
  • ParekhAB & Putney JW Jr 2005 Store-operated calcium channels. Physiological Reviews85757–810.

  • ParrishWR Stefan CJ & Emr SD 2004 Essential role for the myotubularin-related phosphatase Ymr1p and the synaptojanin-like phosphatases Sjl2p and Sjl3p in regulation of phosphatidylinositol 3-phosphate in yeast. Molecular Biology of the Cell153567–3579.

    • Search Google Scholar
    • Export Citation
  • PatelS Joseph SK & Thomas AP 1999 Molecular properties of inositol 145-trisphosphate receptors. Cell Calcium25247–264.

  • PattersonRL van Rossum DB Ford DL Hurt KJ Bae SS Suh PG Kurosaki T Snyder SH & Gill DL 2002 Phospholipase C-gamma is required for agonist-induced Ca2+ entry. Cell111529–541.

    • Search Google Scholar
    • Export Citation
  • PayrastreB Nievers M Boonstra J Breton M Verkleij AJ & VanBergen en Henegouwen PMP 1992 A differential location of phosphoinositide kinases diacylglycerol kinase and phospholipase C in the nuclear matrix. Journal of Biological Chemistry2675078–5084.

    • Search Google Scholar
    • Export Citation
  • PendariesC Tronchere H Plantavid M & Payrastre B 2003 Phosphoinositide signaling disorders in human diseases. FEBS Letters54625–31.

  • PerryRJ & Ridgway ND 2005 Molecular mechanisms and regulation of ceramide transport. Biochimica Biophysica Acta1734220–234.

  • PitcherJA Freedman NJ & Lefkowitz RJ 1998 G protein-coupled receptor kinases. Annual Review of Biochemistry67653–692.

  • PongsO Lindemeier J Zhu XR Theil T Engelkamp D Krah-Jentgens I Lambrecht H-G Koch KW Schwemer J Rivosecchi R et al.1993 Frequenin a novel calcium-binding protein that modulates synaptic efficacy in the Drosophila nervous system. Neuron1115–28.

    • Search Google Scholar
    • Export Citation
  • PutneyJW Jr 1986 A model for receptor-regulated calcium entry. Cell Calcium71–12.

  • PutneyJW Jr 2004 The enigmatic TRPCs: multifunctional cation channels. Trends in Cell Biology14282–286.

  • RamehLE Tolias KF Duckworth BC & Cantley LC 1997 A new pathway for synthesis of phosphatidylinositol-45-bisphosphate. Nature390192–196.

    • Search Google Scholar
    • Export Citation
  • RaoK Paik WY Zheng L Jobin RM Tomic M Jiang H Nakanishi S & Stojilkovic SS 1997 Wortmannin-sensitive and -insensitive steps in calcium-controlled exocytosis in pituitary gonadotrophs: evidence that myosin light chain kinase mediates calcium-dependent and wortmannin-sensitive gonadotropin secretion. Endocrinology1381440–1449.

    • Search Google Scholar
    • Export Citation
  • RebecchiMJ & Pentyala SN 2000 Structure function and control of phosphoinositide-specific phospholipase C. Physiological Reviews801291–1335.

    • Search Google Scholar
    • Export Citation
  • RevankarCM Cimino DF Sklar LA Arterburn JB & Prossnitz ER 2005 A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science3071625–1630.

    • Search Google Scholar
    • Export Citation
  • RheeSG2001 Regulation of phosphoinositide-specific phospholipase C. Annual Review of Biochemistry70281–312.

  • RidgwayND Dawson PA Ho YK Brown MS & Goldstein JL 1992 Translocation of oxysterol binding protein to Golgi apparatus triggered by ligand binding. Journal of Cell Biology116307–319.

    • Search Google Scholar
    • Export Citation
  • RizzutoR Brini M Murgia M & Pozzan T 1993 Microdomains with high Ca2+ close to IP3-sensitive channels that are sensed by neighboring mitochondria. Science262744–747.

    • Search Google Scholar
    • Export Citation
  • RohacsT Lopes CM Michailidis I & Logothetis DE 2005 PI(45)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nature Neuroscience8626–634.

    • Search Google Scholar
    • Export Citation
  • RoosJ DiGregorio PJ Yeromin AV Ohlsen K Lioudyno M Zhang S Safrina O Kozak JA Wagner SL Cahalan MD et al.2005 STIM1 an essential and conserved component of store-operated Ca2+ channel function. Journal of Cell Biology169435–445.

    • Search Google Scholar
    • Export Citation
  • RouttSM & Bankaitis VA 2004 Biological functions of phosphatidylinositol transfer proteins. Biochemistry and Cell Biology82254–262.

  • RunnelsLW Yue LX & Clapham DE 2002 The TRPM7 channel is inactivated by PIP2 hydrolysis. Nature Cell Biology15370–378.

  • SaiardiA Resnick AC Snowman AM Wendland B & Snyder SH 2005 Inositol pyrophosphates regulate cell death and telomere length through phosphoinositide 3-kinase-related protein kinases. PNAS1021911–1914.

    • Search Google Scholar
    • Export Citation
  • SaitoK Tolias KF Saci A Koon HB Humphries LA Scharenberg A Rawlings DJ Kinet JP & Carpenter CL 2003 BTK regulates PtdIns-45-P2 synthesis: importance for calcium signaling and PI3K activity. Immunity19669–678.

    • Search Google Scholar
    • Export Citation
  • SantagataS Boggon TJ Baird CL Gomez CA Zhao J Shan WS Myszka DG & Shapiro L 2001 G-protein signaling through tubby proteins. Science2922041–2050.

    • Search Google Scholar
    • Export Citation
  • SatoC Hamada K Ogura T Miyazawa A Iwasaki K Hiroaki Y Tani K Terauchi A Fujiyoshi Y & Mikoshiba K 2004 Inositol 145-trisphosphate receptor contains multiple cavities and L-shaped ligand-binding domains. Journal of Molecular Biology336155–164.

    • Search Google Scholar
    • Export Citation
  • SchiavoG Gu QM Prestwich GD Sollner TH & Rothmann JE 1996 Calcium-dependent switching of the specificity of phosphoinositide binding to synaptotagmin. PNAS9313327–13332.

    • Search Google Scholar
    • Export Citation
  • SeachristJL Anborgh PH & Ferguson SS 2000 Beta 2-adrenergic receptor internalization endosomal sorting and plasma membrane recycling are regulated by Rab GTPases. Journal of Biological Chemistry27527221–27228.

    • Search Google Scholar
    • Export Citation
  • ShearsSB1998 The versatility of inositol phosphates as cellular signals. Biochimica Biophysica Acta143649–67.

  • ShearsSB2004 How versatile are inositol phosphate kinases? Biochemical Journal377265–280.

  • ShenoySK McDonald PH Kohout TA & Lefkowitz RJ 2001 Regulation of receptor fate by ubiquitination of activated beta 2-adrenergic receptor and beta-arrestin. Science2941307–1313.

    • Search Google Scholar
    • Export Citation
  • ShinHW Hayashi M Christoforidis S Lacas-Gervais S Hoepfner S Wenk MR Modregger J Uttenweiler-Joseph S Wilm M Nystuen A et al.2005 An enzymatic cascade of Rab5 effectors regulates phosphoinositide turnover in the endocytic pathway. Journal of Cell Biology170607–618.

    • Search Google Scholar
    • Export Citation
  • ShishevaA Sbrissa D & Ikonomov O 1999 Cloning characterization and expression of a novel Zn2+-binding FYVE finger-containing phosphoinositide kinase in insulin-sensitive cells. Molecular and Cellular Biology19623–634.

    • Search Google Scholar
    • Export Citation
  • ShpetnerH Joly M Hartley D & Corvera S 1996 Potential sites of PI-3 kinase function in the endocytic pathway revealed by the PI-3 kinase inhibitor wortmannin. Journal of Cell Biology132595–605.

    • Search Google Scholar
    • Export Citation
  • SimonciniT Hafezi-Moghadam A Brazil DP Ley K Chin WW & Liao JK 2000 Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature407538–541.

    • Search Google Scholar
    • Export Citation
  • SorensenSD Linseman DA McEwen EL Heacock AM & Fisher SK 1998 A role for a wortmannin-sensitive phosphatidylinositol-4-kinase in the endocytosis of muscarinic cholinergic receptors. Molecular Pharmacology53827–836.

    • Search Google Scholar
    • Export Citation
  • StephensLR Smrcka AV Cooke FT Jackson TR Sternweis PC & Hawkins PT 1994 A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta-gamma subunits. Cell7783–93.

    • Search Google Scholar
    • Export Citation
  • StephensLR Eguinoa A Erdjument-Bromage H Lui M Cooke F Coadwell J Smrcka AS Thelen M Cadwallader K Tempst P et al.1997 The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor p101. Cell89105–114.

    • Search Google Scholar
    • Export Citation
  • StoreyMK Byers DM Cook HW & Ridgway ND 1998 Cholesterol regulates oxysterol binding protein (OSBP) phosphorylation and Golgi localization in Chinese hamster ovary cells: correlation with stimulation of sphingomyelin synthesis by 25-hydroxycholesterol. Biochemical Journal336247–256.

    • Search Google Scholar
    • Export Citation
  • StraubSG & Sharp GW 1996 A wortmannin-sensitive signal transduction pathway is involved in the stimulation of insulin release by vasoactive intestinal polypeptide and pituitary adenylate cyclase-activating polypeptide. Journal of Biological Chemistry2711660–1668.

    • Search Google Scholar
    • Export Citation
  • StrubingC Krapivinsky G Krapivinsky L & Clapham DE 2001 TRPC1 and TRPC5 form a novel cation channel in mammalian brain. Neuron29645–655.

    • Search Google Scholar
    • Export Citation
  • SuhBC & Hille B 2002 Recovery from muscarinic modulation of M current channels requires phosphatidylinositol 45-bisphosphate synthesis. Neuron35507–520.

    • Search Google Scholar
    • Export Citation
  • SuireS Coadwell J Ferguson GJ Davidson K Hawkins P & Stephens L 2005 p84 a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ. Cu rrent Biology15566–570.

    • Search Google Scholar
    • Export Citation
  • TaylorCW & Laude AJ 2002 IP3 receptors and their regulation by calmodulin and cytosolic Ca2+. Cell Calcium32321–334.

  • TaylorGS & Dixon JE 2003 PTEN and myotubularins: families of phosphoinositide phosphatases. Methods in Enzymology36643–56.

  • TerauchiY Tsuji Y Satoh S Minoura H Murakami K Okuno A Inukai K Asano T Kaburagi Y Ueki K et al.1999 Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nature Genetics21230–235.

    • Search Google Scholar
    • Export Citation
  • ThomasGMH Cunningham E Fensome A Ball A Totty NF Truong O Hsuan JJ & Cockcroft S 1993 An essential role of phosphatidylinositol transfer protein in phospholipase C-mediated inositol lipid signaling. Cell74919–928.

    • Search Google Scholar
    • Export Citation
  • TrotterPJ Wu W-I Pedretti J Yates R & Voelker DR 1998 A genetic screen for aminophospholipid transport mutants identifies the phosphatidylinositol 4-kinase Stt4p as an essential component in phosphatidylserine metabolism. Journal of Biological Chemistry27313189–13196.

    • Search Google Scholar
    • Export Citation
  • TuckerWC & Chapman ER 2002 Role of synaptotagmin in Ca2+-triggered exocytosis. Biochemical Journal3661–13.

  • van DamEM Ten Broeke T Jansen K Spijkers P & Stoorvogel W 2002 Endocytosed transferrin receptors recycle via distinct dynamin and phosphatidylinositol 3-kinase-dependent pathways. Journal of Biological Chemistry27748876–48883.

    • Search Google Scholar
    • Export Citation
  • van RossumDB Patterson RL Sharma S Barrow RK Kornberg M Gill DL & Snyder SH 2005 Phospholipase Cgamma1 controls surface expression of TRPC3 through an intermolecular PH domain. Nature43499–104.

    • Search Google Scholar
    • Export Citation
  • VerbskyJW Chang SC Wilson MP Mochizuki Y & Majerus PW 2005 The pathway for the production of inositol hexakisphosphate in human cells. Journal of Biological Chemistry2801911–1920.

    • Search Google Scholar
    • Export Citation
  • ViardP Butcher AJ Halet G Davies A Nurnberg B Heblich F & Dolphin AC 2004 PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nature Neuroscience7939–946.

    • Search Google Scholar
    • Export Citation
  • VieiraOV Verkade P & Simons K 2005 FAPP2 is involved in the transport of apical cargo in polarized MDCK cells. Journal of Cell Biology170521–526.

    • Search Google Scholar
    • Export Citation
  • VihtelicTS Goeb M Milligan S O’Tousa JE & Hyde DR 1993 Localization of Drosophila retinal degeneration B a membrane-associated phosphatidylinositol transfer protein. Journal of Cell Biology1221013–1022.

    • Search Google Scholar
    • Export Citation
  • VoelkerDR2005 Bridging gaps in phospholipid transport. Trends in Biochemical Sciences30396–404.

  • WalentJH Porter BW & Martin TF 1992 A novel 145 kd brain cytosolic protein reconstitutes Ca(2+)-regulated secretion in permeable neuroendocrine cells. Cell70765–775.

    • Search Google Scholar
    • Export Citation
  • WangYJ Li WH Wang J Xu K Dong P Luo X & Yin HL 2004 Critical role of PIP5KIγ 87 in InsP3-mediated Ca(2+) signaling. Journal of Cell Biology1671005–1010.

    • Search Google Scholar
    • Export Citation
  • WaselleL Gerona RR Vitale N Martih TF Bader MF & Regazzi R 2005 Role of phosphoinositide signaling in the control of insulin exocytosis. Molecular Endocrinology193097–3106.

    • Search Google Scholar
    • Export Citation
  • WattSA Kular G Fleming IN Downes CP & Lucocq JM 2002 Subcellular localization of phosphatidylinositol 45-bisphosphate using the pleckstrin homology domain of phospholipase C delta1. Biochemical Journal363657–666.

    • Search Google Scholar
    • Export Citation
  • WeiYJ Sun HQ Yamamoto M Wlodarski P Kunii K Martinez M Barylko B Albanesi JP & Yin HL 2002 Type II phosphatidylinositol 4-kinase beta is a cytosolic and peripheral membrane protein that is recruited to the plasma membrane and activated by Rac-GTP. Journal of Biological Chemistry27746586–46593.

    • Search Google Scholar
    • Export Citation
  • WeiszOA Gibson GA Leung SM Roder J & Jeromin A 2000 Overexpression of frequenin a modulator of phosphatidylinositol 4-kinase inhibits biosynthetic delivery of an apical protein in polarized madin-darby canine kidney cells. Journal of Biological Chemistry27524341–24347.

    • Search Google Scholar
    • Export Citation
  • WenkMR & De Camilli P 2004 Protein–lipid interactions and phosphoinositide metabolism in membrane traffic: insights from vesicle recycling in nerve terminals. PNAS1018262–8269.

    • Search Google Scholar
    • Export Citation
  • WenkMR Pellegrini L Klenchin VA Di Paolo G Chang S Daniell L Arioka M Martin TF & De Camilli P 2001 PIP kinase Igamma is the major PI(45)P2 synthesizing enzyme at the synapse. Neuron3179–88.

    • Search Google Scholar
    • Export Citation
  • WesPD Chevesich J Jeromin A Rosenberg C Stetten G & Montell C 1995 TRPC1 a human homolog of a Drosophila store-operated channel. PNAS929652–9656.

    • Search Google Scholar
    • Export Citation
  • WhittersEA Cleves AE McGee TP Skinner HB & Bankaitis VA 1993 SAC1p is an integral membrane protein that influences the cellular requirement for phospholipid transfer protein function and inositol in yeast. Journal of Cell Biology12279–94.

    • Search Google Scholar
    • Export Citation
  • WiedemannC Schä fer T & Burger MM 1996 Chromaffin granule-associated phosphatidylinositol 4-kinase activity is required for stimulated secretion. EMBO Journal152094–2101.

    • Search Google Scholar
    • Export Citation
  • WongK Meyers R & Cantley LC 1997 Subcellular localization of phosphatidylinositol 4-kinase isoforms. Journal of Biological Chemistry27213236–13241.

    • Search Google Scholar
    • Export Citation
  • XuC Watras J & Loew LM 2003 Kinetic analysis of receptor-activated phosphoinositide turnover. Journal of Cell Biology161779–791.

  • YanoH Nakanishi S Kimura K Hanai N Saitoh Y Fukui Y Nonomura Y & Matsuda Y 1993 Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells. Journal of Biological Chemistry26825846–25856.

    • Search Google Scholar
    • Export Citation
  • YorkSJ Armbruster BN Greenwell P Petes TD & York JD 2005 Inositol diphosphate signaling regulates telomere length. Journal of Biological Chemistry2804264–4269.

    • Search Google Scholar
    • Export Citation
  • ZhangH He C Yan X Mirshaki T & Logothetis DE 1999 Activation of inwardly rectifying K+ channels by distinct PtdIns(45)P2 interactions. Nature Cell Biology1183–188.

    • Search Google Scholar
    • Export Citation
  • ZhangH Craciun LC Mirshahi T Rohacs T Lopes CM Jin T & Logothetis DE 2003 PIP(2) activates KCNQ channels and its hydrolysis underlies receptor-mediated inhibition of M currents. Neuron37963–975.

    • Search Google Scholar
    • Export Citation
  • ZhangJ Barak LS Anborgh PH Laporte SA Caron MG & Ferguson SS 1999 Cellular trafficking of G protein-coupled receptor/beta-arrestin endocytic complexes. Journal of Biological Chemistry27410999–11006.

    • Search Google Scholar
    • Export Citation
  • ZhuX Jiang M Peyton M Boulay G Hurst R Stefani E & Birnbaumer L 1996 Trp a novel mammalian gene family essential for agonist-activated capacitative Ca2+ entry. Cell85661–671.

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

      Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 983 276 16
PDF Downloads 168 92 9
  • View in gallery

    Updated version of the classical ‘PI cycle’. Plasma membrane PtdIns(4,5)P2 is hydrolyzed by PLC enzymes, after receptor stimulation, to generate two second messengers, Ins(1,4,5)P3 and DAG. Ins(1,4,5)P3, which mobilizes intracellular Ca2+, is rapidly degraded by sequential dephosphorylations to yield myo-inositol. (A fraction of the Ins(1,4,5)P3 is converted to higher inositol phosphates via pathways that differ between plants, yeast and vertebrates (Shears 2004), but it is not shown in the figure for better clarity.) Some of the dephosphorylating enzymes on the pathway of Ins(1,4,5)P3 degradation are sensitive to inhibition by Li+ ions, a finding that led to the idea that the therapeutic effects of Li+ in bipolar disorder might be related to altered signaling affecting primarily hyperactive receptors (Berridge et al. 1989). DAG, the other product of PtdnIns(4,5)P2 hydrolysis, activates PKC enzymes (and some other effectors, such as ion channels or protein kinase D (PKD) – not shown) before being converted to PtdA by DAG-kinase enzymes. PtdA of the plasma membrane can also activate certain effectors (not shown). In the endoplasmic reticulum (ER), PtdA is converted to CDP-DAG, which is conjugated with myo-inositol by PI synthase enzyme(s). When cells are stimulated in the presence of Li+, CDP-DAG accumulates because of the shortage of myo-inositol derived from phosphoinositide hydrolysis. The PtdIns of the ER is transferred to the plasma membrane by PI transfer proteins, but it is less clear whether a similar mechanism transfers PtdA between the membranes. Most downstream pathways in this messenger system are regulated by PKC and other Ca2+-responsive protein kinases or phosphatases.

  • View in gallery

    G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) activate PtdIns(4,5)P2 hydrolysis by distinct mechanisms, the former using G protein-mediated activation of PLCβ isoforms, and the latter causing PLCγ activation. Ins(1,4,5)P3 binds to its receptors located primarily in the ER in the form of tetrameric Ca2+ channels releasing Ca2+ from the internal stores. The N-terminal Ins(1,4,5)P3-binding domain of the InsP3 receptor is probably in close proximity to the C-terminal channel domain with a long intervening regulatory domain (see insert). Emptying of the ER Ca2+ pools relays information (by unknown mechanisms) to plasma membrane Ca2+ channels, commonly termed store-operated Ca2+ channels (SOC), to enhance Ca2+ influx into the cell. Members of the TRP family of Ca2+ channels may function as SOC, and it has been suggested that there is a physical regulatory contact between plasma membrane-adjacent InsP3 receptors and certain TRP channels (see text for details). Another spatial organization is related to the ‘coupling’ of Ca2+ release via the InsP3 receptors with uptake by mitochondria that are juxtaposed to InsP3 receptor-rich ER domains.

  • View in gallery

    The network of interconversions between phosphoinositides. Phosphoinositides are phosphorylated (red arrows) by inositide kinases and are dephosphorylated (blue arrows) by phosphoinositide phosphatases. Most (but not all) of the kinases are quite specific and phosphorylate only one substrate in a specific position on the inositol ring. Some kinases (such as the class II PI 3-kinases, PI3KC2) show wider substrate tolerance in vitro but are likely to have a clear substrate preference in vivo. The substrate specificity of most (but not all) phosphatases is less stringent in vitro, and some can dephosphorylate lipids as well as the soluble inositol phosphates. The physiologic and preferred substrate is not known for all inositide phosphatases, nor is it known in all cases which enzyme or enzymes are primarily responsible for a specific interconversion step. For example, Sac1 phosphatases can remove the 3- and 4-phosphates from a mono-phosphorylated inositol lipid, but synaptojanins (Snj), which are primarily known as 5-phosphatases, also contain a Sac1 phosphatase motif and can function as Sac1 phosphatases (Guo et al. 1999). Since myotubularin-related inositol lipid phosphatases (MTMRs) (Taylor & Dixon 2003) also dephosphorylate the 3 position on PtdIns(3)P, it is likely that PtdIns(3)P is dephosphorylated by Sac1, Snj-s and MTMRs in different cellular compartments (Parrish et al. 2004). This figure indicates only the more established routes; for all other possibilities of interconversion, see Abel et al.(2001).

  • View in gallery

    The general scheme of endocytosis from the plasma membrane. Transmembrane proteins (e.g. receptors) associate with adapter proteins capable of recognizing the internalization signal (usually within their membrane-adjacent cytoplasmic sequence). (Often, a covalent modification, such as phosphorylation or ubiquitination, takes place at these sites on the transmembrane proteins – not shown here.) The adapter protein interaction is also aided by the presence of membrane phosphoinositides and requires an active small GTP-binding protein (such as Arfs or Rabs). The adapter protein also binds clathrin, thereby recruiting the protein into clathrin-coated pits. Several adapter proteins have been shown to bind phosphoinositides, which, in most cases, are the most abundant PtdIns(4,5)P2. Once the vesicles are pinched off (clathrin-coated vesicles, CV), this lipid is no longer demonstrable in the vesicles and is replaced by 3-phosphorylated inositides, contributing to a new identity of the vesicles. Recent studies also indicate that PtdIns(3,4,5)P3 formed in the membrane can be a source of 3-phosphorylated lipids in the endosomes after sequential dephosphorylations by vesicle-associated phosphatases that remove the 5- and 4- phosphates (Ivetac et al. 2005, Shin et al. 2005). Multivesicular bodies are formed from early endosomes (EE) after inward invagination and budding, and PtdIns(3,5)P2 is a critical component of this process (see text for more details).

  • View in gallery

    Multiple steps in the exocytic process. Secretory vesicles containing their cargo become docked to the plasma membrane to form the rapidly releasable vesicular pool by maturation. During maturation, which is an ATP-dependent process, these vesicles become ‘primed’, that is, ready for release once the Ca2+-induced triggering takes place. Synthesis of phosphoinositides (probably PtdIns(4,5)P2) is part of the priming process, and the recruitment of the Ca2+-binding regulatory protein CAPS (which also binds PtdIns(4,5)P2) is an essential component of priming. Vesicles are stabilized by the t- and v-snare proteins (syntaxin and VAMP respectively), and they respond to Ca2+ increases via synaptotagmin (a protein also capable of phosphoinositide binding), which ultimately triggers the conformational change(s) leading to pore opening and cargo release. Phosphoinositides as well as Ca2+ increases act at multiple steps, and production of the lipid both at the membrane and on the surface of the vesicles may take place.

  • AbelK Anderson RA & Shears SB 2001 Phosphatidylinositol and inositol phosphate metabolism. Journal of Cell Science1142207–2208.

  • AlessiDR James SR Downes CP Holmes AB Gaffney PR Reese CB & Cohen P 1997 Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Current Biology7261–269.

    • Search Google Scholar
    • Export Citation
  • AoyagiK Sugaya T Umeda M Yamamoto S Terakawa S & Takahashi M 2005 The activation of exocytotic sites by the formation of phosphatidylinositol 45-bisphosphate microdomains at syntaxin clusters. Journal of Biological Chemistry28017346–17352.

    • Search Google Scholar
    • Export Citation
  • BaiJ Tucker WC & Chapman ER 2004 PIP2 increases the speed of response of synaptotagmin and steers its membrane-penetration activity toward the plasma membrane. Nature Structural and Molecular Biology1136–44.

    • Search Google Scholar
    • Export Citation
  • BallaT1998 Phosphatidylinositol 4-kinases. Biochimica Biophysica Acta143669–85.

  • BallaA Tuymetova G Barshishat M Geiszt M & Balla T 2002 Characterization of type II phosphatidylinositol 4-kinase isoforms reveals association of the enzymes with endosomal vesicular compartments. Journal of Biological Chemistry27720041–22050.

    • Search Google Scholar
    • Export Citation
  • BallaA Tuymetova G Tsiomenko A Varnai P & Balla T 2005 A plasma membrane pool of phosphatidylinositol 4-phosphate is generated by phosphatidylinositol 4-kinase type-III alpha: studies with the PH domains of the oxysterol binding protein and FAPP1. Molecular Biology of the Cell161282–1295.

    • Search Google Scholar
    • Export Citation
  • BankaitisVA Cortese J Phillips SE & Alb JG Jr 2004 Phosphatidylinositol transfer protein function in the mouse. Advances in Enzyme Regulation44201–218.

    • Search Google Scholar
    • Export Citation
  • BarylkoB Gerber SH Binns DD Grichine N Khvotchev M Sudhof TC & Albanesi JP 2001 A novel family of phosphatidylinositol 4-kinases conserved from yeast to humans. Journal of Biological Chemistry2767705–7708.

    • Search Google Scholar
    • Export Citation
  • BerridgeMJ1984 Inositol trisphosphate and diacylglycerol as intracellular messengers. Biochemical Journal220345–360.

  • BerridgeMJ Downes CP & Hanley MR 1989 Neural and developmental actions of lithium: a unifying hypothesis. Cell59411–419.

  • BezprozvannyI Watras J & Ehrlich BE 1991 Bell-shaped calcium-response curves of Ins(145)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature351751–754.

    • Search Google Scholar
    • Export Citation
  • BezzeridesVJ Ramsey IS Kotecha S Greka A & Clapham DE 2004 Rapid vesicular translocation and insertion of TRP channels. Nature Cell Biology6709–720.

    • Search Google Scholar
    • Export Citation
  • BiL Okabe I Bernard DJ Wynshaw-Boris A & Nussbaum RL 1999 Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110 alpha subunit of phosphoinositide 3-kinase. Journal of Biological Chemistry27410963–10968.

    • Search Google Scholar
    • Export Citation
  • BiL Okabe I Bernard DJ & Nussbaum RL 2002 Early embryonic lethality in mice deficient in the p110 beta catalytic subunit of PI 3-kinase. Mammalian Genome13169–172.

    • Search Google Scholar
    • Export Citation
  • BoehningD & Joseph SK 2000 Direct association of ligand-binding and pore domains in homo- and heterotetrameric inositol 145-trisphosphate receptors. EMBO Journal195450–5459.

    • Search Google Scholar
    • Export Citation
  • BonifacinoJS & Weissman AM 1998 Ubiquitin and the control of protein fate in the secretory and endocytic pathways. Annual Review of Cell and Developmental Biology1419–57.

    • Search Google Scholar
    • Export Citation
  • BonifacinoJS & Traub LM 2003 Signals for sorting of transmembrane proteins to endosomes and lysosomes. Annual Review of Biochemistry72395–447.

    • Search Google Scholar
    • Export Citation
  • BosanacI Alattia JR Mal TK Chan J Talarico S Tong FK Tong KI Yoshikawa F Furiuchi T Iwai M et al.2002 Structure of the inositol 145-trishphosphate receptor binding core in complex with its ligand. Nature420696–700.

    • Search Google Scholar
    • Export Citation
  • BosanacI Yamazaki H Matsu-ura T Michikawa T Mikoshiba K & Ikura M 2005 Crystal structure of the ligand binding suppressor domain of type 1 inositol 145-trisphosphate receptor. Molecular Cell17193–203.

    • Search Google Scholar
    • Export Citation
  • BrownMS & Goldstein JL 1974 Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. Journal of Biological Chemistry2497306–7314.

    • Search Google Scholar
    • Export Citation
  • BrownMS & Goldstein JL 1979 Receptor-mediated endocytosis: insights from the lipoprotein receptor system. PNAS763330–3337.

  • BrownMS & Goldstein JL 1999 A proteolytic pathway that controls the cholesterol content of membranes cells and blood. PNAS9611041–11048.

    • Search Google Scholar
    • Export Citation
  • CarmanCV Barak LS Chen C Liu-Chen L-Y Onorato JJ Kennedy SP Caron MG & Benovic JL 2000 Mutational analysis of Gβγ and phospholipid interaction with G protein-coupled receptor kinase 2. Journal of Biological Chemistry27510443–10452.

    • Search Google Scholar
    • Export Citation
  • CarrollK Gomez C & Shapiro L 2004 Tubby proteins: the plot thickens. Nature Reviews. Molecular Cell Biology555–63.

  • CheminJ Patel AJ Duprat F Lauritzen I Lazdunski M & Honore E 2005 A phospholipid sensor controls mechanogating of the K+ channel TREK-1. EMBO Journal2444–53.

    • Search Google Scholar
    • Export Citation
  • ChongLD Traynor-Kaplan A Bokoch GM & Schwartz MA 1994 The small GTP-binding protein Rho regulates a phosphatidylinositol 4-phosphate 5-kinase in mammalian cells. Cell79507–513.

    • Search Google Scholar
    • Export Citation
  • ChuangHH Prescott ED Kong H Shields S Jordt SE Basbaum AI Chao MV & Julius D 2001 Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(45)P2-mediated inhibition. Nature411957–962.

    • Search Google Scholar
    • Export Citation
  • ChungSH Song WJ Kim K Bednarski JJ Chen J Prestwich GD & Holz RW 1998 The C2 domains of Rabphilin3A specifically bind phosphatidylinositol 45-bisphosphate containing vesicles in a Ca2+-dependent manner. In vitro characteristics and possible significance. Journal of Biological Chemistry27310240–10248.

    • Search Google Scholar
    • Export Citation
  • CockcroftS1981 Does phosphatidylinositol breakdown control the Ca2+-gating mechanism? Trends in Pharmacological Sciences2340–342.

  • CremonaO Di Paolo G Wenk MR Luthi A Kim WT Takei K Daniell L Nemoto Y Shears SB Flavell RA et al.1999 Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell99179–188.

    • Search Google Scholar
    • Export Citation
  • CsordasG Thomas AP & Hajnoczky G 1999 Quasi-synaptic calcium signal transmission between endoplasmic reticulum and mitochondria. EMBO Journal1896–108.

    • Search Google Scholar
    • Export Citation
  • da FonsecaPC Morris SA Nerou EP Taylor CW & Morris EP 2003 Domain organization of the type 1 inositol 145-trisphosphate receptor as revealed by single-particle analysis. PNAS1003936–3941.

    • Search Google Scholar
    • Export Citation
  • DaleLB Seachrist JL Babwah AV & Ferguson SS 2004 Regulation of angiotensin II type 1A receptor intracellular retention degradation and recycling by Rab5 Rab7 and Rab11 GTPases. Journal of Biological Chemistry27913110–13118.

    • Search Google Scholar
    • Export Citation
  • DaubH Weiss FU Wallasch C & Ullrich A 1996 Role of transactivation of the EGF receptor in signalling by G-protein-coupled receptors. Nature379557–560.

    • Search Google Scholar
    • Export Citation
  • DawsonAP & Irvine RF 1984 Inositol(145)trisphosphate-promoted Ca2+ release from microsomal fractions of rat liver. Biochemical Biophysical Research Communications120858–864.

    • Search Google Scholar
    • Export Citation
  • DikicI2003 Mechanisms controlling EGF receptor endocytosis and degradation. Biochemical Society Transactions311178–1181.

  • Di PaoloG Moskowitz HS Gipson K Wenk MR Voronov S Obayashi M Flavell R Fitzsimonds RM Ryan TA & De Camilli P 2004 Impaired PtdIns(45)P2 synthesis in nerve terminals produces defects in synaptic vesicle trafficking. Nature431415–422.

    • Search Google Scholar
    • Export Citation
  • DowlerS Currie RA Campbell DG Deak M Kular G Downes CP & Alessi DR 2000 Identification of pleckstrin-homology-domain-containing proteins with novel phosphoinositide-binding specificities. Biochemical Journal35119–31.

    • Search Google Scholar
    • Export Citation
  • EberhardDA Cooper CL Low MG & Holz RW 1990 Evidence that the inositol phospholipids are necessary for exocytosis. Biochemical Journal26815–25.

    • Search Google Scholar
    • Export Citation
  • FrankeTF Kaplan DR Cantley LC & Toker A 1997 Direct regulation of the Akt protooncogene product by PI(34)P2. Science275665–668.

  • FrumanDA Meyers RE & Cantley LC 1998 Phosphoinositide kinases. Annual Review of Biochemistry67481–507.

  • FrumanDA Mauvais-Jarvis F Pollard DA Yballe CM Brazil D Bronson RT Kahn CR & Cantley LC 2000 Hypoglycaemia liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nature Genetics26379–382.

    • Search Google Scholar
    • Export Citation
  • FuruichiT Yoshikawa S Miyawaki A Wada K Maeda N & Mikoshiba K 1989 Primary structure and functional expression of the inositol 145-trisphosphate-binding protein P400. Nature34232–38.

    • Search Google Scholar
    • Export Citation
  • GaborikZ & Hunyady L 2004 Intracellular trafficking of hormone receptors. Trends in Endocrinology and Metabolism15286–293.

  • GaidarovI Krupnick JG Falck JR Benovic JL & Keen JH 1999 Arrestin function in G protein-coupled receptor endocytosis requires phosphoinositide binding. EMBO Journal18871–881.

    • Search Google Scholar
    • Export Citation
  • GalvanDL Borrego-Diaz E Perez PJ & Mignery GA 1999 Subunit oligomerization and topology of the inositol 145-trisphosphate receptor. Journal of Biological Chemistry27429483–29492.

    • Search Google Scholar
    • Export Citation
  • GervaisV Lamour V Jawhari A Frindel F Wasielewski E Dubaele S Egly J-M Thierry J-C Kieffer B & Poterszman A 2004 TFIIH contains a PH domain involved in DNA nucleotide excision repair. Nature Structural and Molecular Biology11616–622.

    • Search Google Scholar
    • Export Citation
  • GlouchankovaL Krishna UM Potter BV Falck JR & Bezprozvanny I 2000 Association of the inositol (145)-trisphosphate receptor ligand binding site with phosphatidylinositol (45)-bisphosphate and adenophostin A. Molecular Cell Biology Research Communication3153–158.

    • Search Google Scholar
    • Export Citation
  • GodiA Di Campi A Konstantakopoulos A Di Tullio G Alessi DR Kular GS Daniele T Marra P Lucocq JM & De Matteis MA 2004 FAPPs control Golgi-to-cell-surface membrane traffic by binding to ARF and PtdIns(4)P. Nature Cell Biology6393–404.

    • Search Google Scholar
    • Export Citation
  • GongLW Di Paolo G Diaz E Cestra G Diaz ME Lindau M De Camilli P & Toomre D 2005 Phosphatidylinositol phosphate kinase type I gamma regulates dynamics of large dense-core vesicle fusion. PNAS1025204–5209.

    • Search Google Scholar
    • Export Citation
  • GozaniO Karuman P Jones DR Ivanov D Cha J Logovskoy AA Baird CL Zhu H Field SJ Lessnick SL et al.2003 The PHD finger of the chromatin-associated protein ING2 functions as a nuclear phosphoinositide receptor. Cell11499–111.

    • Search Google Scholar
    • Export Citation
  • GrishaninRN Kowalchyk JA Klenchin VA Ann K Earles CA Chapman ER Gerona RR & Martin TF 2004 CAPS acts at a prefusion step in dense-core vesicle exocytosis as a PIP2 binding protein. Neuron43551–562.

    • Search Google Scholar
    • Export Citation
  • GromadaJ Bark C Smidt K Efanov AM Janson J Mandic SA Webb DL Zhang W Meister B Jeromin A et al.2005 Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta. PNAS10210303–10308.

    • Search Google Scholar
    • Export Citation
  • GuillemetteG Balla T Baukal AJ & Catt KJ 1988 Characterization of inositol 145-trisphosphate receptors and calcium mobilization in a hepatic plasma membrane fraction. Journal of Biological Chemistry2634541–4548.

    • Search Google Scholar
    • Export Citation
  • GuoJ Wenk MR Pellegrini L Onofri F Benfenati F & De Camilli P 2003 Phosphatidylinositol 4-kinase type IIalpha is responsible for the phosphatidylinositol 4-kinase activity associated with synaptic vesicles. PNAS1003995–4000.

    • Search Google Scholar
    • Export Citation
  • GuoS Stolz LE Lemrow SM & York JD 1999 SAC1-like domains of yeast SAC1 INP52 and INP53 and of human synaptojanin encode polyphosphoinositide phosphatases. Journal of Biological Chemistry27412990–12995.

    • Search Google Scholar
    • Export Citation
  • HaglundK Di Fiore PP & Dikic I 2003 Distinct monoubiquitin signals in receptor endocytosis. Trends in Biochemical Sciences28598–603.

  • HajnoczkyG & Thomas AP 1994 The inositol trisphosphate calcium channel is inactivated by inositol trisphosphate. Nature370474–477.

  • HajnoczkyG Robb-Gaspers LD Seitz MB & Thomas AP 1995 Decoding of cytosolic calcium oscillations in the mitochondria. Cell82415–424.

  • HamiltonBA Smith DJ Mueller KL Kerrebrock AW Bronson RT van Berkel V Daly MJ Kruglyak L Reeve MP Nemhauser JL et al.1997 The vibrator mutation causes neurodegeneration via reduced expression of PITP alpha: positional complementation cloning and extragenic suppression. Neuron18711–722.

    • Search Google Scholar
    • Export Citation
  • HanadaK Kumagai K Yasuda S Miura Y Kawano M Fukasawa M & Nishijima M 2003 Molecular machinery for non-vesicular trafficking of ceramide. Nature426803–809.

    • Search Google Scholar
    • Export Citation
  • HardieRC2003 Regulation of TRP channels via lipid second messengers. Annual Review of Physiology65735–759.

  • HayJC & Martin TFJ 1993 Phosphatidylinositol transfer protein required for ATP-dependent priming of Ca2+-activated secretion. Nature366572–575.

    • Search Google Scholar
    • Export Citation
  • HayJC Fisette PL Jenkins GH Fukami K Takenawa T Anderson RA & Martin TFJ 1995 ATP-dependent inositide phosphorylation required for Ca2+-activated secretion. Nature374173–177.

    • Search Google Scholar
    • Export Citation
  • HendricksKB Wang BQ Schnieders EA & Thorner J 1999 Yeast homologue of neuronal frequenin is a regulator of phosphatidylinositol 4-OH-kinase. Nature Cell Biology1234–241.

    • Search Google Scholar
    • Export Citation
  • HickeL2001 A new ticket for entry into budding vesicles –ubiquitin. Cell106527–530.

  • HilgemannDW & Ball R 1996 Regulation of cardiac Na+ Ca2+ exchange and KATP potassium channels by PIP2. Science273956–959.

  • HinchliffeAK Ciruela A & Irvine RF 1998 PIPkins their substrates and their products: new functions for old enzymes. Biochimica Biophysica Acta143687–104.

    • Search Google Scholar
    • Export Citation
  • HolzRW Hlubek MD Sorensen SD Fisher SK Balla T Ozaki S Prestwich GD Stuenkel EL & Bittner MA 2000 A pleckstrin homology domain specific for Ptdins-45-P2 and fused to green fluorescent protein identifies plasma membrane Ptdins-45-P2 as being important in exocytosis. Journal of Biological Chemistry27517878–17885.

    • Search Google Scholar
    • Export Citation
  • HondaA Nogami M Yokozeki T Yamazaki M Nakamura H Watanabe H Kawamoto K Nakayama K Morris AJ Frohman MA et al.1999 Phosphatidylinositol 4-phosphate 5-kinase alpha is a downstream effector of the small G protein ARF6 in membrane ruffle formation. Cell99521–532.

    • Search Google Scholar
    • Export Citation
  • HorowitzLF Hirdes W Suh BC Hilgemann DW Mackie K & Hille B 2005 Phospholipase C in living cells: activation inhibition Ca2+ requirement and regulation of M current. Journal of General Physiology126243–262.

    • Search Google Scholar
    • Export Citation
  • HothM & Penner R 1992 Depletion of intracellular calcium stores activates a calcium current in mast cells. Nature355353–356.

  • HuangCL Feng S & Hilgemann DW 1998 Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gbetagamma. Nature391803–806.

    • Search Google Scholar
    • Export Citation
  • HunyadyL Baukal AJ Gaborik Z Olivares-Reyes JA Bor M Szaszak M Lodge R Catt KJ & Balla T 2002 Differential PI 3-kinase dependence of early and late phases of recycling of the internalized AT1 angiotensin receptor. Journal of Cell Biology1571211–1222.

    • Search Google Scholar
    • Export Citation
  • IrvineRF2003 Nuclear lipid signalling. Nature Reviews. Molecular Cell Biology4349–360.

  • IvetacI Munday AD Kisseleva MV Zhang XM Luff S Tiganis T Whisstock JC Rowe T Majerus PW & Mitchell CA 2005 The type Ialpha inositol polyphosphate 4-phosphatase generates and terminates phosphoinositide 3-kinase signals on endosomes and the plasma membrane. Molecular Biology of the Cell162218–2233.

    • Search Google Scholar
    • Export Citation
  • JiangQ-X Thrower EC Chester DW Ehrlich BE & Sigworth FJ 2002 Three-dimensional structure of the type 1 inositol 145-trisphosphate receptor at 24 A resolution. EMBO Journal213575–3581.

    • Search Google Scholar
    • Export Citation
  • JolyM Kazlauskas A Fay FS & Corvera S 1994 Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science263684–687.

    • Search Google Scholar
    • Export Citation
  • KatzmannDJ Odorozzi G & Emr SD 2002 Receptor downregulation and multivesicular-body sorting. Nature Reviews. Molecular Cell Biology3893–905.

    • Search Google Scholar
    • Export Citation
  • KiselyovK Xu X Mozhayeva G Kuo T Pessah I Migniery G Zhu X Birnbaumer L & Muallem S 1998 Functional interaction between InsP3 receptors and store-operated Htrp3 channels. Nature396478–482.

    • Search Google Scholar
    • Export Citation
  • KorehK & Monaco ME 1986 The relationship of hormone-sensitive and hormone-insensitive phosphatidylinositol to phosphatidylinositol 45-bisphosphate in the WRK-1 cell. Journal of Biological Chemistry26188–91.

    • Search Google Scholar
    • Export Citation
  • KrapivinskyG Gordon EA Wickman K Velimirovic B Krapivinsky L & Clapham DE 1995 The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K(+)-channel proteins. Nature374135–141.

    • Search Google Scholar
    • Export Citation
  • KrylovaIN Sablin EP Moore J Xu RX Waitt GM MacKay JA Juzumiene D Bynum JM Madauss K Montana V et al.2005 Structural analyses reveal phosphatidylinositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell120343–355.

    • Search Google Scholar
    • Export Citation
  • LagaceTA Byers DM Cook HW & Ridgway ND 1997 Altered regulation of cholesterol and cholesteryl ester synthesis in Chinese-hamster ovary cells overexpressing the oxysterol-binding protein is dependent on the pleckstrin homology domain. Biochemical Journal326205–213.

    • Search Google Scholar
    • Export Citation
  • LeeA Frank DW Marks MS & Lemmon MA 1999 Dominant-negative inhibition of receptor-mediated endocytosis by a dynamin-1 mutant with a defective pleckstrin homology domain. Current Biology9261–264.

    • Search Google Scholar
    • Export Citation
  • LeeS-J Xu H Kang L-W Amzel LM & Montell C 2003 Light adaptation through phosphoinositide-regulated translocation of Drosophila visual arrestin. Neuron39121–132.

    • Search Google Scholar
    • Export Citation
  • LefkowitzRJ1993 G protein-coupled receptor kinases. Cell74409–412.

  • LehtoM & Olkkonen VM 2003 The OSBP-related proteins: a novel protein family involved in vesicle transport cellular lipid metabolism and cell signalling. Biochimica Biophysica Acta16311–11.

    • Search Google Scholar
    • Export Citation
  • LemmonMA & Ferguson KM 2000 Signal-dependent membrane targeting by pleckstrin homology (PH) domains. Biochemical Journal3501–18.

  • LeopoldtD Hanck T Exner T Maier U Wetzker R & Nurnberg B 1998 Gβγ stimulates phosphoinositide 3-kinase-gamma by direct interaction with two domains of the catalytic p110 subunit. Journal of Biological Chemistry2737024–7029.

    • Search Google Scholar
    • Export Citation
  • LiY Choi M Cavey G Daugherty J Suino K Kovach A Bingham NC Kliewer SA & Xu EH 2005 Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Molecular Cell17491–502.

    • Search Google Scholar
    • Export Citation
  • LintschingerB Balzer-Geldsetzer M Baskaran T Graier WF Romanin C Zhu MX & Groschner K 2000 Coassembly of Trp1 and Trp3 proteins generates diacylglycerol- and Ca2+-sensitive cation channels. Journal of Biological Chemistry27527799–27805.

    • Search Google Scholar
    • Export Citation
  • LiouJ Kim ML Heo WD Jones JT Myers JW Ferrell JE Jr & Meyer T 2005 STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Current Biology151235–1241.

    • Search Google Scholar
    • Export Citation
  • LitvakV Dahan N Ramachandran S Sabanay H & Lev S 2005 Maintenance of the diacylglycerol level in the Golgi apparatus by the Nir2 protein is critical for Golgi secretory function. Nature Cell Biology7225–234.

    • Search Google Scholar
    • Export Citation
  • LiuB Zhang C & Qin F 2005 Functional recovery from desensitization of vanilloid receptor TRPV1 requires resynthesis of phosphatidylinositol 45-bisphosphate. Journal of Neuroscience254835–4843.

    • Search Google Scholar
    • Export Citation
  • LiuX Singh BB & Ambudkar IS 2003 TRPC1 is required for functional store-operated Ca2+ channels. Role of acidic amino acid residues in the S5–S6 region. Journal of Biological Chemistry27811337–11343.

    • Search Google Scholar
    • Export Citation
  • LopesCM Rohacs T Czirjak G Balla T Enyedi P & Logothetis DE 2005 PIP2 hydrolysis underlies agonist-induced inhibition and regulates voltage gating of two-pore domain K+ channels. Journal of Physiology (Lond)564117–129.

    • Search Google Scholar
    • Export Citation
  • LoyetKM Kowalchyk JA Chaudhary A Chen J Prestwitch GD & Martin TF 1998 Specific binding of phosphatidylinositol 45-bisphosphate to calcium-dependent activator protein for secretion (CAPS) a potential phosphoinositide effector protein for regulated exocytosis. Journal of Biological Chemistry2738337–8343.

    • Search Google Scholar
    • Export Citation
  • LuoJ Field SJ Lee JY Engelman JA & Cantley LC 2005 The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. Journal of Cell Biology170455–464.

    • Search Google Scholar
    • Export Citation
  • LuttrellLM & Lefkowitz RJ 2002 The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. Journal of Cell Science115455–465.

    • Search Google Scholar
    • Export Citation
  • MaedaN Kawasaki T Nakade S Yokota N Taguchi T Kasai M & Mikoshiba K 1991 Structural and functional characterization of inositol 145-trisphosphate receptor channel from mouse cerebellum. Journal of Biological Chemistry2661109–1116.

    • Search Google Scholar
    • Export Citation
  • MajerusPW Kisseleva MV & Norris FA 1999 The role of phosphatases in inositol signaling reactions. Journal of Biological Chemistry27410669–10672.

    • Search Google Scholar
    • Export Citation
  • MakDO & Foskett JK 1994 Single-channel inositol 145-trisphosphate receptor currents revealed by patch clamp of isolated Xenopus oocyte nuclei. Journal of Biological Chemistry26929375–29378.

    • Search Google Scholar
    • Export Citation
  • ManzoliL Martelli AM Billi AM Faenza I Fiume R & Cocco L 2005 Nuclear phospholipase C: involvement in signal transduction. Progress in Lipid Research44185–206.

    • Search Google Scholar
    • Export Citation
  • MarcheseA & Benovic JL 2001 Agonist-promoted ubiquitination of the G protein-coupled receptor CXCR4 mediates lysosomal sorting. Journal of Biological Chemistry27645509–45512.

    • Search Google Scholar
    • Export Citation
  • MartinTF2003 Tuning exocytosis for speed: fast and slow modes. Biochimica Biophysica Acta1641157–165.

  • MartinTFJ Loyet KM Barry VA & Kowalchik JA 1997 The role of PtdIns(45)P2 in exocytotic membrane fusion. Biochemical Society Transactions251137–1141.

    • Search Google Scholar
    • Export Citation
  • McPhersonPS Garcia EP Slepnev VI David C Zhang X Grabs D Sossin WS Bauerfeind R Nemoto Y & De Camilli P 1996 A presynaptic inositol-5-phosphatase. Nature379353–357.

    • Search Google Scholar
    • Export Citation
  • MeunierFA Osborne SL Hammond GR Cooke FT Parker PJ Domin J & Schiavo G 2005 Phosphatidylinositol 3-kinase C2α is essential for ATP-dependent priming of neurosecretory granule exocytosis. Molecular Biology of the Cell164841–4851.

    • Search Google Scholar
    • Export Citation
  • MichellRH1982 Is phosphatidylinositol really out of the calcium gate? Nature296492–493.

  • MigneryGA & Sudhof TC 1990 The ligand binding site and transduction mechanism in the inositol-145-triphosphate receptor. EMBO Journal93893–3898.

    • Search Google Scholar
    • Export Citation
  • MigneryGA Sudhof TC Takei K & De Camilli P 1989 Putative receptor for inositol 145-trisphosphate similar to ryanodine receptor. Nature342192–195.

    • Search Google Scholar
    • Export Citation
  • MikoshibaK1993 Inositol 145-trisphosphate receptor. Trends in Pharmacological Sciences1486–89.

  • MikoshibaK1997 The InsP3 receptor and intracellular signaling. Current Opinion in Neurobiology7339–345.

  • MilosevicI Sorensen JB Lang T Krauss M Nagy G Haucke V Jahn R & Neher E 2005 Plasmalemmal phosphatidylinositol-45-bisphosphate level regulates the releasable vesicle pool size in chromaffin cells. Journal of Neuroscience252557–2565.

    • Search Google Scholar
    • Export Citation
  • MoraA Komander D Van Aalten DM & Alessi DR 2004 PDK1 the master regulator of AGC kinase signal transduction. Seminars in Cellular and Developmental Biology15161–170.

    • Search Google Scholar
    • Export Citation
  • MoriY Wakamori M Miyakawa T Hermosura M Hara Y Nishida M Hirose K Mizushima A Kurosaki M Mori E et al.2002 Transient receptor potential 1 regulates capacitative Ca2+ entry and Ca2+ release from endoplasmic reticulum in B lymphocytes. Journal of Experimental Medicine195673–681.

    • Search Google Scholar
    • Export Citation
  • Naga PrasadSV Laporte SA Chamberlain D Caron MG Barak L & Rockman HL 2002 Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. Journal of Cell Biology158563–575.

    • Search Google Scholar
    • Export Citation
  • Naga PrasadSV Jayatilleke A Madamanchi A & Rockman HA 2005 Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nature Cell Biology7785–796.

    • Search Google Scholar
    • Export Citation
  • NakanishiS Catt KJ & Balla T 1995 A wortmannin-sensitive phosphatidylinositol 4-kinase that regulates hormone-sensitive pools of inositolphospholipids. PNAS925317–5321.

    • Search Google Scholar
    • Export Citation
  • NishizukaY1988 The molecular heterogeneity of protein kinase C and its implications for cellular regulation. Nature34661–665.

  • OdaH Murayama T & Nomura Y 1997 Inhibition of protein kinase C-dependent noradrenaline release by wortmannin in PC12 cells. Archives in Biochemistry and Biophysics33796–102.

    • Search Google Scholar
    • Export Citation
  • OdomAR Stahlberg A Wente SR & York JD 2000 A role for nuclear inositol 145-trisphosphate kinase in transcriptional control. Science2872026–2029.

    • Search Google Scholar
    • Export Citation
  • OdorozziG Babst M & Emr SD 1998 Fab1p PtdIns(3)P 5-kinase function essential for protein sorting in the multivesicular body. Cell95847–858.

    • Search Google Scholar
    • Export Citation
  • OkamotoM & Sudhof TC 1997 Mints Munc18-interacting proteins in synaptic vesicle exocytosis. Journal of Biological Chemistry27231459–31464.

    • Search Google Scholar
    • Export Citation
  • OlkkonenVM & Lehto M 2004 Oxysterols and oxysterol binding proteins: role in lipid metabolism and atherosclerosis. Annals of Medicine36562–572.

    • Search Google Scholar
    • Export Citation
  • OlsenHL Hoy M Zhang W Bertorello AM Bokvist K Capito K Efanov AM Meister B Thams P Yang SN et al.2003 Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells. PNAS1005187–5192.

    • Search Google Scholar
    • Export Citation
  • OtsuM Hiles I Gout I Fry MJ Ruiz-Larrea F Panayotou G Thompson A Dhand R Hsuan JJ et al.1991 Characterization of two 85 kDa proteins that associate with receptor tyrosine kinases middle-T/pp60c-src complexes and PI3-kinase. Cell6591–104.

    • Search Google Scholar
    • Export Citation
  • OwenDJ Collins BM & Evans PR 2004 Adaptors for clathrin coats: structure and function. Annual Review of Cell and Developmental Biology20153–191.

    • Search Google Scholar
    • Export Citation
  • PacherP & Hajnoczky G 2001 Propagation of the apoptotic signal by mitochondrial waves. EMBO Journal204107–4121.

  • PadronD Wang YJ Yamamoto M Yin H & Roth MG 2003 Phosphatidylinositol phosphate 5-kinase Ibeta recruits AP-2 to the plasma membrane and regulates rates of constitutive endocytosis. Journal of Cell Biology162693–701.

    • Search Google Scholar
    • Export Citation
  • ParekhAB & Putney JW Jr 2005 Store-operated calcium channels. Physiological Reviews85757–810.

  • ParrishWR Stefan CJ & Emr SD 2004 Essential role for the myotubularin-related phosphatase Ymr1p and the synaptojanin-like phosphatases Sjl2p and Sjl3p in regulation of phosphatidylinositol 3-phosphate in yeast. Molecular Biology of the Cell153567–3579.

    • Search Google Scholar
    • Export Citation
  • PatelS Joseph SK & Thomas AP 1999 Molecular properties of inositol 145-trisphosphate receptors. Cell Calcium25247–264.

  • PattersonRL van Rossum DB Ford DL Hurt KJ Bae SS Suh PG Kurosaki T Snyder SH & Gill DL 2002 Phospholipase C-gamma is required for agonist-induced Ca2+ entry. Cell111529–541.

    • Search Google Scholar
    • Export Citation
  • PayrastreB Nievers M Boonstra J Breton M Verkleij AJ & VanBergen en Henegouwen PMP 1992 A differential location of phosphoinositide kinases diacylglycerol kinase and phospholipase C in the nuclear matrix. Journal of Biological Chemistry2675078–5084.