Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Corticotropin-releasing factor (CRF) is the principal neuroregulator of the hypothalamic-pituitary-adrenocortical axis and plays an important role in coordinating the endocrine, autonomic, and behavioral responses to stress and immune challenge. We report here the cloning of a cDNA coding for a CRF receptor from a human corticotropic tumor library. The cloned cDNA encodes a 415-amino acid protein comprising seven putative membrane-spanning domains and is structurally related to the calcitonin/vasoactive intestinal peptide/growth hormone-releasing hormone subfamily of G protein-coupled receptors. The receptor expressed in COS cells binds rat/human CRF with high affinity (Kd = 3.3 +/- 0.45 nM) and specificity and is functionally coupled to adenylate cyclase. The CRF antagonist alpha-helCRF-(9-41) inhibits the CRF-stimulated increase in intracellular cAMP. Northern blot analysis reveals that the CRF receptor is expressed in the rat pituitary and brain as well as in the mouse AtT20 corticotropic cells. We also describe an alternatively spliced form of the receptor which includes an insert of 29 amino acids in the first intracellular loop.
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PMID:Expression cloning of a human corticotropin-releasing-factor receptor. 769 41

Galanin is a widely distributed 29/30 amino acid long neuropeptide with multiple biological effects. It inhibits glucose-induced insulin release, hippocampal acetylcholine release, hippocampal glutamate but not GABA release, and it lowers spinal excitability and firing of locus coeruleus neurons. It stimulates food (fat) intake and growth hormone release upon hypothalamic or i.c.v. injection. Galanin actions are mediated via high affinity Gi/G0 protein-coupled receptors--involving effector systems such as K(+)-, Ca(2+)-channels and adenylate cyclase. Galanin receptor agonists are thought to have therapeutic application in treatment of chronic pain and prevention of ischemic damage; galanin receptor antagonists have therapeutic potential in the treatment of Alzheimer's disease, depression, and feeding disorders.
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PMID:Galanin--a neuroendocrine peptide. 769 57

To elucidate the mechanisms of the impaired pituitary response to growth hormone-releasing hormone (GHRH) in aged animals on a cellular basis, a reverse hemolytic plaque assay was performed on dispersed pituitary cells from young (8-month-old) and old (26-month-old) male F344 rats. The proportion of growth hormone (GH)-plaque forming somatotropes, i.e., actually functioning somatotropes, was reduced in old rats to 50-60% of that in young rats under both unstimulated and GHRH-stimulated conditions. The response of dispersed cells to GHRH, however, seemed to remain unchanged with age when expressed as a percent increase of plaque-forming cells from the basal value. The mean diameter of plaques, which reflects the average amount of GH secreted from a single cell, was not smaller in old rats under either the unstimulated or stimulated conditions. There was also no difference between the two age groups in the frequency distribution of the plaque size of functioning somatotropes. The stimulation by forskolin, a compound that directly activates membrane-bound adenylate cyclase and consequently provokes the cyclic adenosine-3',5'-monophosphate (cAMP) pathway for GH secretion in somatotropes, produced almost the same results as those by GHRH stimulation. It was concluded, therefore, that the impaired response of the pituitary gland to GHRH could be due mostly to a reduction in the density of functioning somatotropes rather than to impairments in steps of the GHRH-cAMP signal pathway in somatotropes .
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PMID:The growth hormone-releasing hormone-cyclic adenosine-3',5'-monophosphate signal pathway in somatotropes is practically intact during aging. 770 May

In old mammals, including humans, the spontaneous growth hormone (GH) secretory pattern is markedly reduced resulting in lower amounts of GH released over 24 h, and the GH response to administration of GH-releasing hormone (GHRH) is reduced. In agreement with these in vivo findings, an impaired responsiveness to GHRH is evident in the pituitary of old male and female rats in vitro, and this is linked with a diminished stimulation of adenylate cyclase by GHRH. The poor GH responsiveness to GHRH in old mammals, which in the rat is coupled to a defective number of GHRH receptors in the somatotrophs, is likely due to a primary deficiency of GHRH availability, as implied by the diminished GHRH immunoreactivity and gene expression in and GHRH release from the hypothalamus of old rats. Attempts have been made to stimulate the sluggish somatotrophic function in elderly humans and dogs using GHRH; in either species positive results were obtained though, overall, it would seem that the GHRH hypofunction does not entirely account for the GH hyposecretory state during ageing. Concerning somatostatin, although the expression of this peptide decreases with age in the rat hypothalamus, secretion and activity of this hormone is increased, resulting in an altered relationship between GHRH and somatostatin gene expression and secretion. It is likely that defects, especially in catecholaminergic and cholinergic neurons, are instrumental in altering specific peptidergic neurons. Reportedly, catecholamines induce GH release by stimulating GHRH neurons and inhibiting somatostatin-releasing neurons; acetylcholine stimulates GH release via muscarinic receptors, in this way inhibiting the action of somatostatin neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Somatotropic dysregulation in old mammals. 772 Dec 60

In vitro lipolysis by chicken adipose explants was stimulated by growth hormone (GH) or glucagon. Adenosine or the adenosine agonist, N6-phenylisopropyladenosine (PIA), inhibited GH stimulated lipolysis, the effect of adenosine not being observed in the presence or adenosine deaminase. Glucagon induced lipolysis was also reduced by PIA. It is suggested that adenosine may act by Gi linked to either adenylate cyclase (for glucagon) or the signal transduction mechanism for GH. Lipolysis was not stimulated by GH in the presence of phenylephrine (alpha 1 adrenergic agonist), isoproterenol (beta adrenergic agonist), adrenaline or glucagon. Although the presence of p-amino clonidine (alpha 2 adrenergic agonist) depressed basal lipolysis, a response to GH was still present. Either glucagon or beta-adrenergic agonists (isoproterenol, adrenaline) stimulated lipolysis. In both cases, GH attenuated the lipolytic response to these hormones, which act via a cyclic adenosine monophosphate signal transduction mechanism.
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PMID:Influence of adenosine or adrenergic agonists on growth hormone stimulated lipolysis by chicken adipose tissue in vitro. 774 92

Young rats were fed on an essential fatty acid (EFA)-deprived diet for 6 weeks after weaning. Their pituitary was removed and adenohypophyseal cells dispersed and maintained in culture. Membrane lipids were analyzed and basal and stimulated levels of hormone secretion were measured after 4-day incubation in a culture medium containing or not 160 microM arachidonic acid 20:4n-6 (AA) in order to obtain EFA-deficient or EFA-restored pituitary cells, respectively. In EFA-deficient cells membrane phosphoglycerides (PGL) were depleted in AA and adrenic acid 22:4n-6; the deficit was overcome by incubation in the presence of AA. Depletion diversely affected PGL classes. AA was highly depleted in choline phosphoglycerides (ChoPG), only moderately depleted in serine and ethanolamine phosphoglycerides (SerPG and EtnPG) and not depleted at all in inositol phosphoglycerides, suggesting preferential preservation of AA in that class of PGL. Restoration of AA by addition of the fatty acid to the culture medium was complete for ChoPG and EtnPG and only partial for SerPG. Depressed levels of AA and adrenic acid in PGL were compensated for by a concomitant increase in 20:3n-9 and 22:3n-9. Growth hormone and prolactin (PRL) secretion was assessed by radioimmunoassay and possible effects of a membrane AA deficit on hormone regulation were tested in cells challenged by either growth hormone-releasing hormone, thyrotropin-releasing hormone, angiotensin II (AII), vasoactive intestinal peptide (VIP) or dopamine. Neither basal nor stimulated growth hormone secretion was different from controls in EFA-deficient cells. PRL modulation by VIP or dopamine was not affected either in EFA-deficient cells. In contrast, the capacity of AII, but not of thyrotropin-releasing hormone, to release PRL was markedly decreased in EFA-deprived cells. It was restored by addition of AA to the incubation medium. Parallel depression of AII-induced inositol phosphates and cAMP accumulation was also observed after EFA deficiency. When tested on membranes, the paradoxical inhibition of adenylate cyclase by AII documented by previous observations was reinforced in EFA-deficient membranes. In contrast, binding of AII was not affected by EFA deficiency. It is concluded that under our experimental conditions EFA deficiency affects selectively coupling of the AII receptor to its effectors without alteration of binding. The effect could involve changes in receptor interactions with coupling proteins.
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PMID:Selective effect of a diet-induced decrease in the arachidonic acid membrane-phospholipid content on in vitro phospholipase C and adenylate cyclase-mediated pituitary response to angiotensin II. 782 82

Signal transduction mechanisms involved in mouse growth hormone-releasing hormone (GRH) and somatostatin (SRIH) release were investigated using an in vitro perifusion system. Hypothalamic fragments were exposed to depolarizing agents, protein kinase A and C activators, and a calcium ionophore. The depolarizing agents, KCl (60 mM) and veratridine (50 microM), induced similar patterns of GRH and SRIH release. Somatostatin release in response to both agents was twofold greater than that of GRH. Forskolin (10 microM and 100 microM), an adenylate cyclase activator, stimulated both GRH and SRIH release, though with different secretory profiles. The SRIH response was prolonged and persisted beyond removal of the drug from the system, while the GRH response was brief, ending even prior to forskolin removal. Neither GRH nor SRIH were stimulated by 1,9-dideoxy-forskolin (100 microM), a forskolin analog with cAMP-independent actions. A23187 (5 microM), a calcium ionophore, stimulated the release of SRIH to a much greater extent than that of GRH. The GRH and SRIH secretory responses to PMA (1 microM), a protein kinase C activator, were similar, though delayed. The results suggest that 1) GRH and SRIH secretion are regulated by both protein kinase A and C pathways, and 2) depolarizing agents are important for the release of both hormones.
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PMID:Mouse hypothalamic growth hormone-releasing hormone and somatostatin responses to probes of signal transduction systems. 790 44

Unlike mammals, the goldfish is unique in having dopamine (DA) D1 receptors in the anterior pituitary. In this species, DA stimulates growth hormone (GH) release via D1 receptors coupled to the cAMP-dependent pathway. To further examine the postreceptor mechanisms of this novel pituitary DA D1 system, the role of extracellular Ca2+ ([Ca2+]e] in mediating DA D1-stimulated GH release was studied using dispersed goldfish pituitary cells. The GH responses to DA (1 nM-10 microM), the D1 agonist SKF38393 (1 microM), and the Ca2+ ionophore A23187 (10 microM) were abolished by incubation with Ca(2+)-deficient medium. Incubation with depolarizing doses of KCl (10-25 mM), which activate voltage-sensitive Ca2+ channels (VSCC), induced GH release in a dose-dependent manner. In contrast, the VSCC blockers nifedipine (10 microM), nicardipine (10 microM), and verapamil (10 microM) and the inorganic competitor of Ca2+ entry CoCl2 (5 mM) blocked the GH responses to DA (1 microM) as well as SKF38393 (1 microM). These results strongly indicate that the entry of [Ca2+]e via VSCC is an essential part of the signal transduction mechanisms mediating DA D1-stimulated GH release in the goldfish. In this study, the possible interactions between the Ca(2+)- and cAMP-dependent pathways in DA-induced GH secretion were also investigated. The membrane-permeant cAMP analogue 8Br.cAMP (1 mM) and the adenylate cyclase activator forskolin (10 microM) stimulated GH release from goldfish pituitary cells. These GH responses were suppressed by incubation with Ca(2+)-deficient medium or with the VSCC blocker nifedipine (10 microM). Furthermore, the GH responses to forskolin (10 microM) and the nonselective DA agonist apomorphine (1 microM) were not additive to that of the Ca2+ ionophore A23187 (10 microM). These results suggest that [Ca2+]e entry induced by DA D1 stimulation occur at steps after activation of the cAMP-dependent pathway.
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PMID:Entry of extracellular calcium mediates dopamine D1-stimulated growth hormone release from goldfish pituitary cells. 792 40

Mutations of Gs are found in 30 to 40% of the pituitary tumours responsible for acromegaly (somatotrope tumor), 10% of secreting thyroid tumors, and in the rare McCune-Albright syndrome. Gs is a member of the G protein family, which plays a major role in the mechanism of action of many hormones by coupling their membrane receptors to molecules called effectors, which general intracellular second messengers. Gs is responsible for the coupling of many receptors to adenylate cyclase which synthetizes cyclic AMP. The effect of the mutations of Gs is to permanently activate adenylate cyclase by a mechanism similar to the one exerted by cholera toxin. In the somatotrope cells adenylate cyclase is normally under the control of the hypothalamic hormone GH-RH, which stimulates both growth hormone secretion and cell proliferation. The mutations of Gs allow the somatotrope to escape from the control by GH-RH and to secrete and proliferate in an autonomous way, which leads to the development of a tumor responsible for acromegaly. The same mechanism explains the presence of Gs mutations in the other types of endocrine tumors. Therefore, the mutations transform the gene of Gs into an oncogene, gsp, which represents the first molecular explanation of an old concept familiar to endocrinologists: the autonomy of the secretion and proliferation of endocrine tumors.
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PMID:[G-proteins and endocrine tumors. The example of acromegaly]. 793 40

The parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor belongs to a newly discovered family of G protein-coupled receptors. Members of this family, which have been isolated from mammals, include the receptors for PTH/PTHrP, calcitonin, secretin, growth hormone-releasing hormone, vasoactive intestinal polypeptide (types 1 and 2), gastric-inhibitory polypeptide, glucagon-like peptide 1, glucagon, corticotropin-releasing factor, and the pituitary adenylate cyclase-activating peptide. Very recently, a receptor with remarkable homology to these mammalian receptors was isolated from the insect Manduca sexta, which indicates considerable conservation of these related proteins during evolution. Thus far the cognate ligands for these receptors are 27- to 46-amino-acid residues in length. Members of this novel receptor family are characterized by seven membrane-spanning domains and at least two conserved sites for N-linked glycosylation. Furthermore, 48-amino-acid residues, including eight extracellular cysteines, are identical in all receptors, and many other residues are highly conserved. The PTH/PTHrP receptor is expressed in a large variety of fetal and adult tissues, binds two ligands (PTH and PTHrP) with high affinity, and activates at least two second-messenger systems (adenylate cyclase and phospholipase C).
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PMID:Molecular cloning and characterization of a parathyroid hormone/parathyroid hormone-related peptide receptor: a member of an ancient family of G protein-coupled receptors. 807 40


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