Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have isolated a cDNA encoding a gastric inhibitory polypeptide (GIP) receptor from a hamster insulinoma (HIT-T15) cDNA library. The hamster GIP receptor is a 462 amino acid protein having seven transmembrane segments. Expression of recombinant of hamster GIP receptors in Chinese hamster ovary (CHO) cells shows that it binds specifically to GIP with high affinity (IC50 = 9.6 nM) and is positively coupled to adenylate cyclase, but not to phospholipase C. RNA blot analysis reveals that a 3.8-kb GIP receptor mRNA is expressed at high levels in rat pancreatic islets as well as in HIT-T15 cells.
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PMID:Hamster gastric inhibitory polypeptide receptor expressed in pancreatic islets and clonal insulin-secreting cells: its structure and functional properties. 781 Dec 36

The HGT-1 gastric cancer cell line was used to determine the actions of protein kinase C on the stimulation of adenylate cyclase by the human histamine H2 receptor, and the receptors for gastric inhibitory polypeptide and truncated glucagon like peptide 1 (TGLP-1). Suspensions of HGT-1 cells were preincubated with the activator of protein kinase C, 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/l), for 10 minutes. The subsequent cyclic adenosine monophosphate (AMP) response to 0.5 mmol/l histamine or 100 nmol/l TGLP-1 was reduced by comparison with control cells preincubated in the absence of TPA. The cyclic AMP response to 100 nmol/l gastric inhibitory polypeptide was enhanced by preincubation with TPA, while the responses to cholera toxin and forskolin were unaffected. Preincubation with pertussis toxin prevented the enhancement of the gastric inhibitory polypeptide response by TPA, suggesting an involvement of an inhibitory guanine nucleotide regulatory subunit of the Gi class, but did not change the inhibition of histamine stimulation. In conclusion, activation of protein kinase C produces a specific inhibition of the effects of histamine and TGLP-1 on adenylate cyclase activity in a human gastric cancer cell line by acting at a site close to their receptors.
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PMID:Protein kinase C inhibits cyclic adenosine monophosphate generation by histamine and truncated glucagon like peptide 1 in the human gastric cancer cell line HGT-1. 839 30

The first aim of the study was to investigate the possibility that a defect on the islet adenosine 3',5'-cyclic monophosphate (cAMP) production could be involved in the failure of the glucose-induced insulin secretion in the neonatal streptozotocin diabetic rats. Exposure to glucose concentration that induced a rise of the cAMP content in the control islets did not elicit any significant increase in cAMP in diabetic islets. Forskolin, isobutyl methylxanthine (IBMX), glucagon, or pertussis toxin amplified the cAMP accumulation and the insulin release to the same extent in both types of islets. Somatostatin, prostaglandin E2, UK-14304, or galanin inhibited cAMP accumulation and insulin release to the same extent in both types of islets. Our second purpose was to investigate whether the use of activators of adenylate cyclase could restore the beta-cell competence to glucose in diabetic rats. The addition of IBMX, glucagon, or gastric inhibitory polypeptide (GIP) to perifused islets of diabetic rats amplified their insulin response to glucose, and a clear biphasic pattern of the release was regained. In conclusion, although there is no major alteration of the functionality of the adenylate cyclase in the beta-cells of the diabetic rats, we have identified a defective glucose-induced cAMP generation that could be explained by a block in the step(s) linking glucose metabolism and activation of adenylate cyclase.
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PMID:Decreased glucose-induced cAMP and insulin release in islets of diabetic rats: reversal by IBMX, glucagon, GIP. 889 61

Secretin, glucagon, gastric inhibitory polypeptide (GIP), and parathyroid hormone (PTH) belong, together with vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase (AC)-activating polypeptide, to a family of peptides (the VIP-secretin-glucagon family), which also includes growth hormone-releasing hormone and exendins. All the members of this peptide family possess a remarkable amino-acid sequence homology, and bind to G-protein-coupled receptors, whose signaling mechanism primarily involves AC/protein kinase A and phospholipase C/protein kinase C cascades. VIP and pituitary AC-activating polypeptide play a role in the regulation of the hypothalamus-pituitary-adrenal (HPA) axis, and in this review we survey findings that also other members of the VIP-secretin-glucagon family may have the same function. Secretin and secretin receptors are expressed in the hypothalamus and pituitary gland, and secretin inhibits adrenocorticotropic hormone (ACTH) release. No evidence is available for the presence of secretin receptors in adrenal glands, but secretin selectively depresses the glucocorticoid response to ACTH of dispersed zona fasciculata-reticularis (ZF/R) cells. Glucagon and glucagon-like peptide-1 are contained in the hypothalamus, and all the components of the HPA axis are provided with glucagon and glucagons-like-1 receptors. These peptides exert a short-term inhibitory effect on stress-induced pituitary ACTH release and depress the ZF/R cell response to ACTH by inhibiting the AC/protein kinase A cascade; they also stimulate hypothalamic arginine-vasopressin release. GIP receptors are present in the ZF/R of the normal adrenals, and are particularly abundant in some types of adrenocortical adenomas and hyperplasias. GIP, through the activation of the AC/protein kinase A cascade, evokes a sizeable glucocorticoid secretagogue effect, leading to the identification of a food/GIP-dependent Cushing's syndrome. PTH and PTH-related protein are expressed in the hypothalamus and pituitary gland, and PTH and PTH-related protein receptors in all the components of the HPA axis. Both peptides enhance ACTH and arginine-vasopressin release, as well as stimulate aldosterone and glucocorticoid secretion of dispersed zona glomerulosa and ZF/R cells, respectively. The involvement of growth hormone-releasing hormone and exendins in the functional regulation of the HPA axis has not yet been extensively investigated.
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PMID:Secretin, glucagon, gastric inhibitory polypeptide, parathyroid hormone, and related peptides in the regulation of the hypothalamus- pituitary-adrenal axis. 1076 61

REGULATION OF INSULIN SECRETION: Beta cells are unique endocrine cells. They respond positively, in terms of insulin secretion, not only to changes in the extracellular glucose concentration, but also to activators of the phospholipase C (cholecystokinin or acetylcholine), and to activators of adenylate cyclase (glucagon, glucagon-like peptide-1, or gastric inhibitory polypeptide). Major messengers which mediate glucose action for insulin release are Ca2+, adenosine triphosphate (ATP) and diacylglycerol (DAG). MAJOR PATHWAYS OF INSULIN RELEASE STIMULATION: There are four major pathways involved in stimulation of insulin release. The first pathway is KATP channel-dependent pathway in which increased blood glucose concentrations and increased b-cell metabolism result in a change in intracellular ATP/ADP ratio. This is a contributory factor in closure of ATP-dependent K+ channels, depolarization of b-cell membrane, in increased voltage-dependent L-type Ca2+ channel activity. Increased Ca2+ influx results in increased intracellular Ca2+ and stimulated insulin release. KATP channel-independent pathway augments Ca(2+) -stimulated insulin secretion of KATP channel-dependent pathway. Major potentiation of release results from hormonal and peptidergic activation of receptors linked to adenylyl cyclase. Adenylyl cyclase activity is stimulated by hormones such as vasoactive intestinal peptide (VIP), glucagon-like peptide-1 (GLP-1), and so on. These hormones, acting via G protein, stimulate adenylyl cyclase, thus causing a rise in cyclic adenosine monophosphate (cAMP) and activation of protein kinase A (PKA). Increased activity of PKA results in potentiation of insulin secretion.
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PMID:[Insulin secretion: mechanisms of regulation]. 1550 94

Elevated plasma homocysteine has been reported in individuals with diseases of the metabolic syndrome including vascular disease and insulin resistance. As homocysteine exerts detrimental effects on endothelial and neuronal cells, this study investigated effects of acute homocysteine exposure on beta-cell function and insulin secretion using clonal BRIN-BD11 beta-cells. Acute insulin release studies in the presence of various test reagents were performed using monolayers of BRIN-BD11 cells and samples assayed by insulin radioimmunoassay. Cellular glucose metabolism was assessed by nuclear magnetic resonance (NMR) analysis following 60-min exposure of BRIN-BD11 cell monolayers to glucose in either the absence or presence of homocysteine. Homocysteine dose-dependently inhibited insulin release at moderate and stimulatory glucose concentrations. This inhibitory effect was reversible at all but the highest concentration of homocysteine. 13C-glucose NMR demonstrated decreased labelling of glutamate from glucose at positions C2, C3 and C4, indicating that the tricarboxylic acid (TCA) cycle-dependent glucose metabolism was reduced in the presence of homocysteine. Homocysteine also dose-dependently inhibited insulinotropic responses to a range of glucose-dependent secretagogues including nutrients (alanine, arginine, 2-ketoisocaproate), hormones (glucagon-like peptide-1 (7-36)amide, gastric inhibitory polypeptide and cholecystokinin-8), neurotransmitter (carbachol), drug (tolbutamide) as well as a depolarising concentration of KCl or elevated Ca2+. Insulin secretion induced by activation of adenylate cyclase and protein kinase C pathways with forskolin and phorbol 12-myristate 13-acetate were also inhibited by homocysteine. These effects were not associated with any adverse action on cellular insulin content or cell viability, and there was no increase in apoptosis/necrosis following exposure to homocysteine. These data indicate that homocysteine impairs insulin secretion through alterations in beta-cell glucose metabolism and generation of key stimulus-secretion coupling factors. The participation of homocysteine in possible beta-cell demise merits further investigation.
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PMID:Detrimental actions of metabolic syndrome risk factor, homocysteine, on pancreatic beta-cell glucose metabolism and insulin secretion. 1664 97


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