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In heterologous expression systems, human GnRH receptors (hGnRHRs) are poorly expressed at the cell surface and this may reflect inefficient exit from the endoplasmic reticulum. Here, we have defined the proportion of GnRHRs at the cell surface using a novel assay based on adenoviral transduction with epitope-tagged GnRHRs followed by staining and semi-automated imaging. We find that in MCF7 (breast cancer) cells, the proportional cell surface expression (PCSE) of hGnRHRs is remarkably low (<1%), when compared with Xenopus laevis (X) GnRHRs (∼40%). This distinction is retained at comparable whole cell expression levels, and the hGnRHR PCSE is increased by addition of the XGnRHR C-tail (h.XGnRHR) or by a membrane-permeant pharmacological chaperone (IN3). The IN3 effect is concentration- and time-dependent and IN3 also enhances the hGnRHR-mediated (but not h.XGnRHR- or mouse GnRHR-mediated) stimulation of [3H]inositol phosphate accumulation and the hGnRHR-mediated reduction in cell number. We also find that the PCSE for hGnRHRs and h.XGnRHRs is low and is greatly increased by IN3 in two hormone-dependent cancer lines, but is higher and less sensitive to IN3 in a gonadotrope line. Finally, we show that the effect of IN3 on hGnRHR PCSE is not mimicked or blocked by two peptide antagonists although they do increase the PCSE for h.XGnRHRs, revealing that an antagonist-occupied cell surface GnRHR conformation can differ from that of the unoccupied receptor. The low PCSE of hGnRHRs and this novel peptide antagonist effect may be important for understanding GnRHR function in extrapituitary sites.
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Fetal glucocorticoids have an important role in the pre-partum maturation of physiological systems essential for neonatal survival such as glucogenesis. Consequently, in clinical practice, synthetic glucocorticoids, like dexamethasone, are given routinely to pregnant women threatened with pre-term delivery to improve the viability of their infants. However, little is known about the effects of maternal dexamethasone treatment on the glucogenic capacity of either the fetus or mother. This study investigated the effects of dexamethasone treatment using a clinically relevant dose and regime on glycogen deposition and the activities of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) in the liver and kidney of pregnant ewes and their fetuses, and of non-pregnant ewes. Dexamethasone administration increased the glycogen content of both the fetal and adult liver within 36 h of beginning treatment. It also increased G6Pase activity in the liver and kidney of the fetuses but not of their mothers or the non-pregnant ewes. Neither hepatic nor renal PEPCK activity was affected by dexamethasone in any group of animals. These changes in glycogen content and G6Pase activity were accompanied by rises in the plasma glucose and insulin concentrations and by a fall in the plasma cortisol level in the fetus and both groups of adult animals. In addition, dexamethasone treatment raised fetal plasma tri-iodothyronine (T3) concentrations and reduced maternal levels of plasma T3 and thyroxine, but had no effect on thyroid hormone concentrations in the non-pregnant ewes. These findings show that maternal dexamethasone treatment increases the glucogenic capacity of both the mother and fetus and has major implications for glucose availability both before and after birth.
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Scheer FAJL Perusquía M Centurion D Buijs RM 2014 The suprachiasmatic nucleus is part of a neural feedback circuit adapting blood pressure response . Neuroscience 266 197 – 207 . ( https://doi.org/10.1016/j.neuroscience.2014.02.018 ) 24583038 10
Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
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Department of Vascular Medicine, Amsterdam Diabetes Centre, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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Hypothalamic Integration Mechanisms, Netherlands Institute for Neuroscience, Amsterdam, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
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Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands
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Kalsbeek A Soeters MR Eggink HM 2017 Bile acid signaling pathways from the enterohepatic circulation to the central nervous system . Frontiers in Neuroscience 11 617 . 10.3389/fnins.2017.00617 29163019 Naqvi SH Nicholas HJ 1970 Conversion
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Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Department of Orthopaedic Surgery, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Department of Physiology, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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Department of Medicine, Medical College of Georgia at Augusta University, Augusta, Georgia, USA
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-induced experimental Parkinson’s-like disease . Journal of Neuroscience 6332 – 6351 . ( https://doi.org/10.1523/JNEUROSCI.0426-16.2016 ) Almeida M Han L Martin-Millan M Plotkin LI Stewart SA Roberson PK Kousteni S O'Brien CA Bellido T Parfitt
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We investigated the effect of the glucocorticoid receptor (GR) antagonist Org 34850 on fast and delayed inhibition of corticosterone secretion in response to the synthetic glucocorticoid methylprednisolone (MPL). Male rats were implanted with a catheter in the right jugular vein, for blood sampling and MPL administration, and with an s.c. cannula for Org 34850 administration. All experiments were conducted at the diurnal hormonal peak in the late afternoon. Rats were connected to an automated sampling system and blood samples were collected every 5 or 10 min. Org 34850 (10 mg/kg, s.c.) or vehicle (5% mulgofen in saline) was injected at 1630 h; 30 min later, rats received an injection of MPL (500 μg/rat, i.v.) or saline (0.1 ml/rat). We found that an acute administration of MPL rapidly decreased the basal corticosterone secretion and this effect was not prevented by acute pretreatment with Org 34850. However, blockade of GR with Org 34850 prevented delayed inhibition of MPL on corticosterone secretion measured between 4 and 12 h after MPL administration. Our data suggest an involvement of GR in modulating delayed, but not fast, inhibition induced by MPL on basal corticosterone secretion.
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Arginine vasopressin (AVP) and corticotropin-releasing hormone (CRH) have both been implicated in modulating insulin secretion from pancreatic β-cells. In the present study, we investigated the insulin-secreting activities of AVP and CRH in wild-type and AVP VIb receptor knockout mice. Both neuropeptides stimulated insulin secretion from isolated mouse pancreatic islets. The response of islets to CRH was increased fourfold by concomitant incubation with a subthreshold dose of AVP that alone did not stimulate insulin secretion. Activation of the endogenously expressed M3 receptor by the cholinergic agonist carbachol also potentiated CRH-induced insulin secretion, indicating that the phenomenon may be pathway specific (i.e. Ca2 +-phospholipase C) rather than agonist specific. The protein kinase C (PKC) inhibitors Ro-31-8425 and bisindolylmaleimide I attenuated the potentiating effect of AVP on CRH-stimulated insulin secretion and blocked AVP-stimulated insulin secretion. A possible interaction between the PKC and protein kinase A pathways was also investigated. The phorbol ester phorbol myristate acetate (PMA) stimulated insulin secretion, while the addition of both PMA and CRH enhanced insulin secretion over that measured with either PMA or CRH alone. Additionally, no AVP potentiation of CRH-stimulated insulin secretion was observed upon incubation in Ca2 +-free Krebs–Ringer buffer. Taken together, the present study suggests a possible synergism between AVP and CRH to release insulin from pancreatic β-cells that relies at least in part on activation of the PKC signaling pathway and is dependent on extracellular Ca2 +. This is the first example of a possible interplay between the AVP and CRH systems outside of the hypothalamic–pituitary–adrenal axis.
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Estradiol-17β (E2) and progesterone (P4) play critical roles in female reproductive physiology and behavior. Given the sensitivity of females to exogenous sources of these steroids, we examined the presence of E2 and P4 in conspecifics' excretions and the transfer of excreted steroids between conspecifics. We paired individual adult female mice with a stimulus male or female conspecific given daily injections of [3H]E2 or [3H]P4. Following 48 h of direct interaction with the stimulus animal, we measured radioactivity in the uterus, ovaries, muscle, olfactory bulbs, mesencephalon and diencephalon (MC+DC), and cerebral cortex of the untreated female cohabitant. Radioactivity was significantly present in all tissues of female subjects after individual exposure to a stimulus male or female given [3H]E2. In females exposed to males given [3H]P4, radioactivity was significantly present in the uterus, ovaries, and muscle, but not in other tissues. In females exposed to stimulus females given [3H]P4, radioactivity was significantly present in all tissues except the MC+DC. In mice directly administered [3H]steroids, greater radioactivity was found in the urine of females than of males. Among females directly administered [3H]steroids, greater radioactivity was found in urine of those given [3H]P4 than of those given [3H]E2. When females were administered unlabeled E2 before exposure to [3H]E2-treated females, less radioactivity was detected in most tissues than was detected in the tissues of untreated females exposed to [3H]E2-treated females. We suggest that steroid transfer among individuals has implications for the understanding of various forms of pheromonal activity.
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Early postnatal events can predispose to metabolic and endocrine disease in adulthood. In this study, we evaluated the programming effects of a single early postnatal oestradiol injection on insulin sensitivity in adult female rats. We also assessed the expression of genes involved in inflammation and glucose metabolism in skeletal muscle and adipose tissue and analysed circulating inflammation markers as possible mediators of insulin resistance. Neonatal oestradiol exposure reduced insulin sensitivity and increased plasma levels of monocyte chemoattractant protein-1 (MCP-1) and soluble intercellular adhesion molecule-1. In skeletal muscle, oestradiol increased the expression of genes encoding complement component 3 (C3), Mcp-1, retinol binding protein-4 (Rbp4) and transforming growth factor β1 (Tgfβ1). C3 and MCP-1 are both related to insulin resistance, and C3, MCP-1 and TGFβ1 are also involved in inflammation. Expression of genes encoding glucose transporter-4 (Glut 4), carnitine-palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor δ (Ppard) and uncoupling protein 3 (Ucp3), which are connected to glucose uptake, lipid oxidation, and energy uncoupling, was down regulated. Expression of several inflammatory genes in skeletal muscle correlated negatively with whole-body insulin sensitivity. In s.c. inguinal adipose tissue, expression of Tgfβ1, Ppard and C3 was decreased, while expression of Rbp4 and Cpt1b was increased. Inguinal adipose tissue weight was increased but adipocyte size was unaltered, suggesting an increased number of adipocytes. We suggest that early neonatal oestrogen exposure may reduce insulin sensitivity by inducing chronic, low-grade systemic and skeletal muscle inflammation and disturbances of glucose and lipid metabolism in skeletal muscle in adulthood.
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The neuropeptide GnRH-I is critical for the regulation of reproduction in all vertebrates. Study of the regulation of GnRH-I in passerine songbirds has been the focus of studies on subjects as diverse as photoperiodism, puberty, stress, nutrition, processing of auditory information, migration, global climate change, and evolutionary biology. Until now, analysis of GnRH-I in songbirds has been limited to measurement of immunoreactive peptide. Measurement of mRNA regulation has been impossible because of lack of knowledge of the GnRH gene sequence, despite many attempts in the last 20 years to identify it. Thus, the relative roles of environmental, social, physiological, and evolutionary influences upon passerine GnRH regulation have remained enigmatic. Here, we report the first cloning of GnRH-I cDNA from a songbird, Taeniopygia guttata, its localization and regulation. Although the homology of its translated precursor polypeptide between chicken GnRH-I precursor polypeptide was only 54%, zebra finch GnRH-I precursor contained an amino acid sequence that can be processed into chicken GnRH-I peptide (pEHWSYGLQPG-amide). In situ hybridization combined with immunocytochemistry showed co-localization of GnRH-I mRNA and immunoreactive peptide in the preoptic area of sexually mature birds. GnRH-I mRNA signal was greatly reduced in sexually immature birds. Ovary mass of female birds was positively correlated with GnRH-I mRNA level in the brain. These data will now permit molecular analysis of the regulation of songbird reproduction by physical, social, and physiological cues, along with fine scale analysis of selection pressures acting upon the reproductive system of songbirds. (244/250).
