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The precise factors involved in the transition of the relaxed pregnant uterus to the contractile state at the onset of parturition remain unclear, but it is accepted that cAMP-generating pathways contribute to uterine relaxation. We have previously reported an increased expression of the adenylyl cyclase (AC)-stimulating protein Galphas in human myometrium during gestation, with a corresponding increase in GTP-stimulated AC activity. However, little is known about the predominating AC isoforms expressed during pregnancy. This information is important, because although all AC isoforms are stimulated by Galphas, their regulation by other signalling molecules is very different. In the present study we have identified the isoforms of AC expressed in both pregnant and non-pregnant myometrium by mRNA analysis and immunoblotting. mRNA encoding for AC I, II, III, VIII and IX was present in non-pregnant and pregnant myometrium, and in cultured myometrial cells. Differing levels of AC protein could be detected in myometrial plasma membranes, with decreased levels of Group 1 (isoforms I, III and VIII) and Group 4 (IX) ACs allied with increased levels of Group 2 (II, IV and VII) and 3 (V and VI) ACs during pregnancy. These findings imply a role for Group 2-activating pathways, e.g. G-protein betagamma-subunits and protein kinase C, in the maintenance of uterine quiescence, whilst suggesting a lesser involvement of calcium-calmodulin complex, an activator of Group 1 AC isoforms, in uterine relaxation during gestation. These data may provide an alternative pharmacological approach for the attenuation of preterm labour.
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ABSTRACT
The possibility that a TSH post-receptor-binding defect is responsible for the pathogenesis of benign thyroid tumours was studied. Thus, we attempted to determine in hyperfunctioning (hot) nodules and non-functioning (cold) nodules whether the functional activity or the amount of G proteins were modified in comparison with surrounding normal tissues. The adenylyl cyclase response to agonists that bypass the TSH–receptor complex (forskolin, guanosine 5′- (β.γ-imido)triphosphate (Gpp(NH)p) or [A1F4]−) was studied on membranes from tumorous and adjacent normal thyroid tissues. We also examined the ability of G proteins to be ADP-ribosylated by cholera toxin (CT) or pertussis toxin (PT), and quantified G proteins by Western blot analysis with specific antisera directed against Gsα and Giα subunits.
Basal adenylyl cyclase activity was unchanged in hot tumours compared with normal tissue whereas the stimulation of adenylyl cyclase by Gpp(NH)p or [A1F4]− (which act directly on Gs) as well as by forskolin (which acts on the catalyst) was significantly (P<0·05) decreased in five of seven nodules studied. Two types of response were found in cold nodules, depending upon whether they were microfollicular or macrofollicular tumours. Basal as well as stimulated adenylyl cyclase activity was increased (0·02<P<0·05) in microfollicular tumours. In contrast, in macrofollicular tumours basal adenylyl cyclase was unchanged whereas stimulated adenylyl cyclase activity was decreased (0·02<P<0·05). The ability of Gs or Gi to be ADP-ribosylated by CT or PT respectively was maintained in tumorous tissue. Quantification of Gs revealed a 30% decrease (P<0·05) in the level of Gs in hot tumours and either an increase or a decrease in cold tumours compared with their respective normal tissue. Quantitative or qualitative changes in Gi protein were also observed, but there was no clear difference between the patients with hot and cold thyroid tumours. A decrease or an increase in adenylyl cyclase activity can therefore be explained by an alteration in the amounts of G proteins, at least in some benign thyroid tumours.
Journal of Endocrinology (1992) 132, 477–485
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SUMMARY
Neutralized acid extracts of the median eminence of the dogfish hypothalamus were found to cause a dose-related activation of adenylyl cyclase in all lobes of the dogfish pituitary. Equal concentrations of extracts of extrahypothalamic areas of the dogfish brain did not activate the enzyme.
The putative neurotransmitters melatonin, serotonin, adrenaline, noradrenaline, dopamine and acetylcholine were without effect, as were the prostaglandins E1 and E2.
The effects of synthetic mammalian hypothalamic hormones were also studied. Both thyrotrophin releasing hormone and gonadotrophin releasing hormone activated the ventral lobe enzyme, but had no effect on the adenylyl cyclase of the other three lobes. The tripeptide, Pro-Leu-Gly-NH2, a possible melanocyte-stimulating hormone release-inhibiting factor had no effect on the enzyme of the neurointermediate lobe.
It is suggested that all four lobes of the dogfish pituitary may be under hypothalamic control and that this control is likely to be mediated by peptide hormones, as in mammals.
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( Fredriksson et al. 2003 ). Signal transduction at the FSHR is mainly mediated by canonical Gs/adenylyl cyclase/cAMP/protein kinase A (PKA) pathway activation, which subsequently leads to cAMP response element-binding protein phosphorylation and gene
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ABSTRACT
The effect of sodium meclofenamate on the binding of [3H]prostaglandin E2 ([3H]PGE2) to membranes from human myometrium was investigated. Meclofenamate inhibited the binding of [3H]PGE2 to high-affinity (dissociation constant 1·5 nmol/l) sites in a reversible dose-dependent manner (inhibition constant 11 μmol/l). The mechanism of inhibition was mainly competitive, but at high doses of meclofenamate (≥ 100 μmol/l) there was loss of PGE receptor sites. Of several PG synthesis inhibitors tested, only meclofenamate and, to a lesser extent, mefenamic acid had a significant inhibitory effect. PGE2 stimulated cyclic AMP generation in slices of human myometrium and this was inhibited by meclofenamate in a dose-dependent manner (50% inhibition occurred at 9 μmol/l). Again, this effect was specific for meclofenamate and fitted a competitive mechanism at doses in the range 1–10 μmol/l and a non-competitive mechanism at higher doses. The data show that meclofenamate, in addition to its traditional role as a PG synthesis inhibitor, affects directly PGE receptor binding and activation.
Journal of Endocrinology (1991) 129, 439–445
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Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
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Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
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Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
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Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
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Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
Geriatric Research, Medicine, Comprehensive Dentistry, Barshop Institute for Longevity and Aging Studies, Education and Clinical Center (182), Audie L. Murphy Division, South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, Texas 78229, USA Departments of
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for increased hepatic fat accumulation in rodents with aging. Catecholamines acting via β-adrenergic receptors (β 1 -, β 2 -, or β 3 -AR subtypes) coupled to adenylyl cyclase and other effectors modulate important biological responses including lipid
Millennium Institute for Fundamental and Applied Biology, Santiago, Chile
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Millennium Institute for Fundamental and Applied Biology, Santiago, Chile
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Millennium Institute for Fundamental and Applied Biology, Santiago, Chile
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Millennium Institute for Fundamental and Applied Biology, Santiago, Chile
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( Nadal et al. 2001 ). Activation of signal transduction cascades by E 2 modulates diverse downstream pathways that have discrete cellular actions, including stimulation of adenylyl cyclase in breast and vascular tissues ( Aronica et al. 1994
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). In this context, the third intracellular cytoplasmic loop is involved in coupling to G proteins and activation of the adenylyl cyclase system ( Takhar et al. 1996 ). Desensitisation of the GLP-1 receptor has been correlated with C-terminal tail
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receptor to stimulate adenylyl cyclase as well as the MAP kinase pathway. Our data revealed that receptors with a deletion of the last 27 or 44 amino acids of the cytoplasmic tail conserved a similar potency and efficacy in stimulating adenylyl cyclase
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GDP for GTP, leading to its activation and dissociation from β- and γ-subunits. (III) The active, GTP-bound form of Gα s /XLα s interacts with and activates transmembrane adenylyl cyclases type I–IX, resulting in increased formation of the second
