Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The AtT-20/D16-16 mouse pituitary tumor cell secretes corticotropin (ACTH) in response to corticotropin-releasing factor (CRF), (-)-isoproterenol, and vasoactive intestinal peptide (VIP). These responses are associated with a rapid increase in cyclic AMP formation. Somatostatin (SRIF) markedly decreases the stimulatory effect of CRF, (-)-isoproterenol, and VIP on both cyclic AMP formation and immunoreactive ACTH secretion. Forskolin and cholera toxin, adenylate cyclase activators, also stimulate cyclic AMP formation and ACTH secretion in AtT-20 cells and these responses are all inhibited by SRIF. The ACTH secretory responses to melittin and to the calcium ionophore A23187, neither of which increases cyclic AMP in AtT-20 cells, were not inhibited by SRIF. SRIF did not affect the binding of a tritiated beta-adrenergic receptor antagonist to AtT-20 membranes nor did it decrease basal cyclic AMP formation even in the presence of excess phosphodiesterase inhibitor, indicating that the reduction of cyclic AMP levels by SRIF did not involve either an interference with beta-adrenergic agonist binding to receptors or stimulation of cyclic AMP degradation. These results indicate that the inhibition of CRF-, (-)-isoproterenol-, and VIP-stimulated ACTH secretion by SRIF may be regulated by its inhibitory action on adenylate cyclase.
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PMID:Somatostatin inhibits multireceptor stimulation of cyclic AMP formation and corticotropin secretion in mouse pituitary tumor cells. 612 32

Somatostatin (SRIF) inhibits both basal and vasoactive intestinal peptide (VIP)-stimulated hormone secretion by the GH4C1 clonal strain of rat pituitary tumor cells. We have previously shown that SRIF inhibits cAMP accumulation stimulated by VIP but does not alter basal cAMP levels in this cell line. To determine the importance of changes in cAMP accumulation in the mechanism of SRIF action, we have compared the effect of SRIF on hormone release stimulated by VIP and two other secretagogues which increase effective intracellular cAMP concentrations: forskolin and 8-Bromo-cAMP (8-Br-cAMP). VIP stimulated GH and PRL secretion to the same maximal extent (220% of control) with similar ED50 values (0.37 +/- 0.03 and 0.43 +/- 0.08 nM, mean +/- SE, respectively). SRIF (100 nM) reduced maximal VIP-stimulation of both GH and PRL release from 220 to 140% of control; however, it did not significantly change the ED50 values for VIP. The effect of SRIF on VIP-stimulated hormone release parallels its action on VIP-stimulated cAMP accumulation. Furthermore, the concentrations of SRIF required to produce half-maximal inhibition of VIP-stimulated GH and PRL release (0.8 +/- 0.2 nM and 0.7 +/- 0.1 nM, respectively) were similar to its potency to inhibit VIP-stimulated cAMP accumulation (1.2 +/- 0.1 nM). These data indicate that changes in cAMP levels mediate inhibition of VIP-stimulated hormone secretion by SRIF. Forskolin increased cAMP accumulation with an ED50 value of 2.4 +/- 0.5 microM. A maximal concentration of forskolin (100 microM) stimulated cAMP accumulation to a greater extent than 100 nM VIP (34 +/- 4-fold vs. 9 +/- 1-fold). Together, forskolin (100 microM) and VIP (100 nM) stimulated cAMP accumulation by more than 50-fold. However, PRL secretion in response to maximal concentrations of VIP or forskolin individually or together were the same (approximately 200% of control). These results support the conclusion that both compounds stimulate PRL secretion by a cAMP-mediated mechanism which can be fully activated by either one alone.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Somatostatin inhibits basal and vasoactive intestinal peptide-stimulated hormone release by different mechanisms in GH pituitary cells. 613 45

Serotonin release from rabbit enterochromaffin cells located in the mucosal epithelium of the small intestine was studied in vitro. Serotonin release from both the serosal and mucosal sides of the small intestine was measured. The addition of muscarinic but not nicotinic cholinergic agonists to the serosal medium resulted in a large but transient increase in serotonin release from the serosal but not the mucosal side of the intestine. Mucosal addition of these agents was ineffective. Serotonin release stimulated by the cholinergic agonist carbachol appeared to be dependent upon influx of extracellular Ca++ for the following reasons: 1) depletion of serosal Ca++ inhibited carbachol-stimulated release; 2) carbachol-stimulated serotonin release was blocked by the inorganic calcium channel blockers Co++, Ni++, Cd++, La and Gd; and 3) serosal serotonin release was increased by the Ca++ ionophore, ionomycin, and by Ba++. The addition of 8-bromoadenosine cyclic AMP or the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, to the serosal medium produced a sustained elevation of serosal serotonin release. 8-bromoadenosine-cyclic AMP-stimulated release was not blocked by depleting extracellular Ca++. Forskolin, a compound which stimulates adenylate cyclase, also stimulated serosal serotonin release. 8-bromoadenosine-cGMP had no effect on serotonin release. Somatostatin (10(-8)-10(-6) M) caused a dose-dependent inhibition of carbachol-stimulated serotonin release. Somatostatin (10(-6) M) only partially inhibited serotonin release stimulated by 8-bromoadenosine-cyclic AMP, 3-isobutyl-1-methylxanthine and forskolin and had no effect on release stimulated by Ba++. The results suggest potential roles for both calcium and cyclic nucleotides in the regulation of serotonin release.
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PMID:Regulation of serotonin release from rabbit intestinal enterochromaffin cells. 614 Mar 9

The effects of forskolin, an adenylate cyclase activator, were investigated on adrenocorticotropin (ACTH) secretion from AtT-20/ D16 -16 mouse pituitary tumor cells. Forskolin increased adenylate cyclase activity in these cells in the absence of added guanyl nucleotide, an effect blocked by somatostatin. Cyclic AMP synthesis and ACTH secretion increased in a concentration-dependent manner, not only in the clonal cells, but in primary cultures of rat anterior pituitary as well. Somatostatin inhibited cyclic AMP synthesis and ACTH secretion in response to forskolin. When forskolin was coapplied with corticotropin releasing factor, cyclic AMP synthesis was potentiated and ACTH secretion additive. The calcium channel blocker, nifedipine, inhibited forskolin, and 8-bromocyclic AMP stimulated ACTH secretion. These data suggest that ACTH secretion may be regulated at the molecular level by changes in cyclic AMP formation, which in turn regulate a calcium gating mechanism.
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PMID:Forskolin stimulates adenylate cyclase activity, cyclic AMP accumulation, and adrenocorticotropin secretion from mouse anterior pituitary tumor cells. 614 27

The cellular and molecular effects of forskolin, a direct, nonhormonal activator of adenylate cyclase, were assessed on the enzyme secretory process in dispersed rat pancreatic acinar cells. Forskolin stimulated adenylate cyclase activity in the absence of guanyl nucleotide. It promoted a rapid and marked increase in cellular accumulation of cyclic AMP alone or in combination with vasoactive intestinal peptide (VIP) but was itself a weak pancreatic agonist and did not increase the secretory response to VIP or other cyclic AMP dependent agonists. Somatostatin was a partial antagonist of forskolin stimulated cyclic AMP synthesis and forskolin plus cholecystokinin-octapeptide (CCK-OP) induced amylase release. Forskolin potentiated amylase secretion in response to calcium-dependent agonists such as CCK-OP, carbachol and A-23187, but did not affect the ability of CCK-OP and (or) carbachol to mobilize 45Ca from isotope preloaded cells; forskolin alone did not stimulate 45Ca release. In calcium-poor media, the secretory response to forskolin and CCK-OP was reduced in a both absolute and relative manner. The data suggests that calcium plays the primary role as intracellular mediator of enzyme secretion and that the role of cyclic AMP may be to modulate the efficiency of calcium utilization.
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PMID:Forskolin potentiates calcium-dependent amylase secretion from rat pancreatic acinar cells. 619 99

Glucagon and glucagon-like peptide-1 (GLP-1) are important regulators of glucose homeostasis, and both are involved in regulating pancreatic islet hormone secretion. Since the sensitivity of the endocrine pancreas to regulatory hormones can be influenced by their receptor number, we have examined the regulation of glucagon receptor and GLP-1 receptor messenger RNA (mRNA) expression in cultured rat pancreatic islets by various factors, including glucose, cAMP, and glucocorticoids. By ribonuclease protection assay we have demonstrated the expression of both glucagon and GLP-1 receptor mRNA in cultured rat islets. We observed a dose-dependent increase in glucagon receptor mRNA expression with increasing glucose concentrations: an approximately 3-fold increase in glucagon receptor mRNA in islets cultured in 22 mM glucose as compared to 3.5 mM glucose. GLP-1 receptor mRNA levels, on the other hand, were not affected by culturing the islets in low glucose concentrations; however, a small, but significant, decrease in GLP-1 receptor mRNA levels was detected when islets were cultured in 20 mM glucose. Forskolin and 3-isobuty-1-methylxanthine, which increase intracellular cAMP levels, caused a 75% reduction in glucagon receptor mRNA expression. Somatostatin 14 and 28, both of which can inhibit intracellular cAMP production, stimulated glucagon receptor mRNA expression by 40% and 75%, respectively. GLP-1 receptor mRNA levels remained unchanged under all conditions that altered intracellular cAMP levels. Finally, in islets cultured in the presence of 10 nM dexamethasone an approximately 50% decrease in both glucagon and GLP-1 receptor mRNA expression was observed. These results indicate that the expression of glucagon and GLP-1 receptor mRNA is differentially regulated in rat pancreatic islets and suggest that regulation of receptor mRNA expression may be an important mechanism for controlling the sensitivity of the islets to glucagon and GLP-1.
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PMID:Regulation of glucagon and glucagon-like peptide-1 receptor messenger ribonucleic acid expression in cultured rat pancreatic islets by glucose, cyclic adenosine 3',5'-monophosphate, and glucocorticoids. 753 5

We characterized somatostatin receptors expressed in hamster glucagonoma INR1G9 cells and the effects of somatostatin on glucagon secretion, proglucagon gene expression, and the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent signal-transduction cascade. 125I-labeled somatostatin was displaced by somatostatin-14 and somatostatin-28 with a dissociation constant of 2 nmol/l. Stable GTP analogues decreased binding of 125I-somatostatin to its receptors, suggesting an interaction of somatostatin receptors with G proteins. Chemical cross-linking of 125I-somatostatin to its receptor revealed a molecular mass of the ligand-receptor complex of 47 kDa. Somatostatin inhibited forskolin-stimulated activation of adenylate cyclase [2.5 microM forskolin (161%) + 1 microM somatostatin (128%); P < 0.05] and protein kinase A [10 microM forskolin (143%) + 1 microM somatostatin (114%); P < 0.05] but did not influence basal activities of these enzymes. Forskolin-induced stimulation of cAMP generation was reduced by somatostatin [2.5 microM forskolin (306%) + 1 microM somatostatin (145%); P < 0.05]. Somatostatin inhibited forskolin, theophylline, and arginine stimulation of glucagon secretion. Basal as well as forskolin-, theophylline-, and isobutyl methylxanthine-induced proglucagon gene expression was significantly reduced by somatostatin. Our data show that, in INR1G9 cells, somatostatin receptors are at least in part coupled to the adenylate cyclase system. Somatostatin is a potent negative regulator of both basal and forskolin-stimulated proglucagon gene expression. The interaction with forskolin occurs at the level of adenylate cyclase. The effect of somatostatin on basal proglucagon gene transcription is most probably mediated by an unrelated second messenger system. Somatostatin may influence several functions of the pancreatic A cell.
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PMID:Functional characterization of somatostatin receptors expressed on hamster glucagonoma cells. 784 Jan 80

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

In the present study we investigated the effects of the somatostatin (SS) analogs octreotide, RC-160, and BIM-23014 on GH release by cultured cells of human GH-secreting pituitary tumors, in normal rat anterior pituitary cells, and on gastrin release by cultured cells from a human gastrinoma. In all GH-secreting adenomas and in rat anterior pituitary cells, RC-160 was the most potent compound. RC-160 significantly inhibited GH-, PRL, and/or alpha-subunit release by human GH-secreting pituitary adenoma cells in concentrations as low as 10(-12)-10(-14) M, whereas at the same concentrations, octreotide and BIM-23014 did not inhibit or were significantly less effective in inhibiting GH release (P < 0.01, RC-160 vs. octreotide and BIM-23014). In rat anterior pituitary cell cultures, the IC50 values for inhibition of GH release were, in rank order of potency, 0.1, 5.3, 47, 48, and 99 pM for RC-160, SS-14, BIM-23014, octreotide, and SS-28, respectively. Maximal inhibitory effects by the three analogs were the same in the human GH adenoma cell cultures and the rat anterior pituitary cell cultures (-60%). On the basis of these data, RC-160 appears to be about 500 times more potent than octreotide and BIM-23014 in inhibiting GH release by rat anterior pituitary cells in vitro. Forskolin (100 microM) as well as pretreatment of the cells with pertussis toxin significantly diminished the inhibitory effects of the three SS analogs and those of SS-14 and SS-28 to the same extent. The latter data suggest that octreotide, RC-160, and BIM-23014 act mainly via a pertussis toxin-sensitive G-protein and an adenylyl cyclase-dependent mechanism. In the human gastrinoma culture, RC-160 inhibited gastrin release significantly more than octreotide at 10(-12)- and 10(-14)-M concentrations (P < 0.01). In conclusion, the SS analogs octreotide, RC-160, and BIM-23014 may have significant different potencies of inhibition of hormone release in vitro, with RC-160 being the most potent SS analog and octreotide and BIM-23014 having similar potencies. Depending on the pharmacokinetic properties of these three octapeptide SS analogs, these observations may have consequences for the medical therapy of patients with SS receptor-positive endocrine tumors.
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PMID:Relative potencies of the somatostatin analogs octreotide, BIM-23014, and RC-160 on the inhibition of hormone release by cultured human endocrine tumor cells and normal rat anterior pituitary cells. 790 31

1. Intracellular recordings were made from submucosal neurones in guinea-pig ileum. In some animals, the extrinsic (sympathetic) nerves to the submucosal plexus were severed 5-7 days previously. The actions of somatostatin and somatostatin analogues on membrane potential, membrane current and inhibitory postsynaptic potentials (IPSPs) were examined. 2. Somatostatin, somatostatin(1-28), [D-Trp8]somatostatin and the somatostatin analogue CGP 23996 all produced equivalent maximum hyperpolarizations or outward currents; half-maximal concentrations (EC50 values) were 9-11 nM. The somatostatin analogue MK 678 had an EC50 of 0.9 nM. Extrinsic sympathectomy did not alter concentration-response relations for somatostatin or its analogues. 3. Somatostatin (> 100 nM) produced hyperpolarization or outward current that declined almost completely during superfusion for 2-4 min; decline of the somatostatin current was exponential with a time constant of 30 s in the presence of 2 microM somatostatin. Desensitization was not altered by extrinsic denervation. 4. Recovery from desensitization was rapid and followed the time course of agonist wash-out. Forskolin, phorbol esters, dithiothreitol, hydrogen peroxide, concanavalin A, or reducing temperature from 35 to 29 degrees C did not alter the time course, degree of, or recovery from desensitization. 5. The somatostatin-induced desensitization was of the homologous type; no cross-desensitization to opiate or alpha 2-adrenoceptor agonists (which activate the same potassium conductance) occurred. 6. Somatostatin desensitization did not alter the adrenergic IPSP seen in sympathetically innervated preparations but abolished the non-adrenergic IPSP recorded from normal preparations and from preparations in which the extrinsic sympathetic nerve supply had been surgically removed. 7. The selective blockade of the non-adrenergic IPSP by the homologous-type somatostatin desensitization characterized in the present study provides strong support for the hypothesis that somatostatin is the neurotransmitter underlying the non-adrenergic IPSP in both normal and extrinsically denervated submucosal neurones.
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PMID:Somatostatin-mediated inhibitory postsynaptic potential in sympathetically denervated guinea-pig submucosal neurones. 790 23


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