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)

Rat anterior pituitary gland adenylyl cyclase activity is stimulated by prostaglandins with an order of potency of PGE1 congruent to PGE2 greater than PGA1 much greater than PGB1 congruent to PGF1 alpha congruent to PGF2 alpha which is the same for cAMP accumulation and growth hormone release. Somatostatin inhibited prostaglandin-stimulated adenylyl cyclase with an ID50 of 1.48 X 10(-8) +/- 0.27 X 10(-8) M. GTP also stimulated adenylyl cyclase activity at concentrations greater than 10(-6) M but did not prevent inhibition by somatostatin. These results indicate that at least one action of somatostatin is exerted directly on cAMP formation.
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PMID:Inhibition of anterior pituitary prostaglandin-stimulated adenylyl cyclase activity by somatostatin. 611 86

To evaluate the effect of chronically elevated adenylyl cyclase, we targeted the expression of a constitutively active mutant alpha-subunit (alpha s+) of Gs to the insulin-producing pancreatic beta-cells of transgenic mice. As assessed by the polymerase chain reaction, expression of alpha s+ mRNA was restricted to the transgenic pancreas. Histological analysis by light microscopy and immunohistochemistry for insulin, glucagon, and somatostatin appeared normal in transgenic islets. Pancreatic insulin content was quantitatively the same for alpha s+ transgenic and control mice. Comparisons of glucose homeostasis, insulin secretion, and islet cAMP revealed the expected differences between alpha s+ transgenic and control mice; in every case, however, responses to glucose alone were normal, and the differences were observed only when measurements were performed in the presence of isobutylmethylxanthine (IBMX), an inhibitor of cAMP phosphodiesterase. 1) In vivo, ip glucose tolerance was normal in alpha s+ transgenics; when ip glucose was preceded by administration of IBMX, the rise in blood glucose was approximately 33% less in the transgenic than in the control mice. 2) Insulin secretion from the perfused pancreas stimulated sequentially with 11 and 22 mM glucose caused characteristic first and second phase insulin release that did not differ between transgenic and control pancreases. IBMX increased biphasic insulin release from all pancreases, but caused a 2-fold greater than normal release from the transgenics. 3) Similarly, batch-incubated alpha s+ and control islets secreted equivalent amounts of insulin in the presence of glucose (22 mM) alone, whereas the combination of glucose plus IBMX was twice as effective on alpha s+ islets. 4) Islet cAMP levels paralleled insulin secretion; in the presence of IBMX, but not glucose alone, cAMP was increased 2-fold more in alpha s+ vs. control islets. We conclude that expression of constitutively active alpha s mutant in pancreatic beta-cells of transgenic mice is functionally effective, causing the physiological phenotype of increased islet cAMP and insulin secretion. However, these changes are uncovered only in the presence of IBMX; without IBMX, glucose homeostasis and islet function appear normal. This normalization, or counterregulation, of cAMP synthesis presumably is accomplished by a compensatory increase in cAMP degradation, possibly via increased activity of cAMP phosphodiesterase.
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PMID:Constitutively active stimulatory G-protein alpha s in beta-cells of transgenic mice causes counterregulation of the increased adenosine 3',5'-monophosphate and insulin secretion. 750 12

Receptors for regulatory peptides (hormones or neurotransmitters) play a pivotal role in the ability of cells to taste the rich neuroendocrine environment of the gut. Recognition of low concentration of peptides with a high specificity and translation of the peptide-receptor interaction into a biological response through different signalling pathways (adenylyl cyclase-cAMP or phospholipase C-phosphatidylinositol) are crucial properties of receptors. While many new receptors have been identified and thereafter characterized functionally during the 1980s, molecular biology now emerges as the privileged way for the structural characterization and discovery of receptors. Different strategies of receptor cloning have been developed which may or may not require prior receptor purification. Among cloning strategies that do not require receptor purification, homology screening of cDNA libraries, expression of receptor cDNA or mRNA in Xenopus laevis oocytes or in COS cells, and the polymerase chain reaction method achieved great success, e.g. cloning of receptors for cholecystokinin, gastrin, glucagon-like peptide 1, gastrin-releasing peptide/bombesin, neuromedin K, neuropeptide Y, neurotensin, opioids, secretin, somatostatin, substance K, substance P and vasoactive intestinal peptide. All these receptors belong to the superfamily of G-protein-coupled receptors which consist of a single polypeptide chain (350-450 amino acids) with seven transmembrane segments, an N-terminal extracellular domain and a C-terminal cytoplasmic domain. In this chapter, we have detailed the properties of three receptors which play an important role in digestive tract physiology and illustrate various signal transduction pathways: pancreatic beta-cell galanin receptors which mediate inhibition of insulin release and intestinal epithelial receptors for vasoactive intestinal peptide and peptide YY, which mediate the stimulation and inhibition of water and electrolyte secretion, respectively.
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PMID:Receptors for gut regulatory peptides. 751 Sep 49

The signal transduction pathways of a cloned human somatostatin receptor subtype, SSTR1, have been investigated in CHO cells stably expressing this receptor. In SSTR1-expressing CHO cells, somatostatin-14 inhibits forskolin-stimulated cAMP formation in a dose-dependent manner with an ED50 of 1.0 x 10(-9) M. Somatostatin-14 also stimulates inositol 1,4,5-trisphosphate formation in a dose-dependent manner with an ED50 of 4.0 x 10(-8) M. Somatostatin-14 inhibitory action on adenylyl cyclase and stimulatory action on inositol 1,4,5-trisphosphate formation are both blocked by pertussis toxin, indicating that these effects of SSTR1 are mediated by pertussis toxin-sensitive G protein(s). Antiserum against Gi alpha 3 blocked the inhibitory effects of somatostatin-14 on forskolin-stimulated adenylyl cyclase, but antiserum against Gi alpha 1/Gi alpha 2 did not, indicating that Gi alpha 3 dominantly couples SSTR1 to adenylyl cyclase. These results demonstrate that SSTR1 can be coupled to different signaling pathways to exert multiple biological effects, one of which is mediated by Gi alpha 3.
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PMID:Multiple effector coupling of somatostatin receptor subtype SSTR1. 752 97

Intracellular recordings were made in submucosal neurons from the guinea pig ileum to study the actions of norepinephrine and somatostatin on slow depolarizations induced by 2-chloroadenosine (CADO) and substance P. Local application (by pressure) of CADO and substance P induced a slow depolarization that occurred concomitantly with an increase in input membrane resistance. Norepinephrine, UK-14304 (alpha 2-adrenoceptor agonist), and somatostatin blocked the excitatory responses induced by CADO in a concentration-dependent manner. The alpha 2-adrenoceptor antagonists idazoxan and yohimbine antagonized these inhibitory effects of UK-14304 and norepinephrine. UK-14304 also decreased depolarizations induced by forskolin, but not those induced by the adenosine 3',5'-cyclic monophosphate analogue 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate. Slow depolarizations induced by substance P were blocked neither by UK-14304 nor by somatostatin. It was previously shown that staurosporine (an inhibitor of various protein kinases) and KT-5720 (an inhibitor of protein kinase A) inhibited slow depolarizations induced by CADO. Here, substance P depolarizations were inhibited by staurosporine and calphostin C (a blocker of protein kinase C) but not by KT-5720. In conclusion, activation of alpha 2-adrenoceptors and somatostatin receptors selectively blocks excitatory responses induced by CADO, most likely by inhibition of adenylyl cyclase and via pertussis toxin-sensitive G proteins. Slow depolarizations induced by substance P are independent of adenylyl cyclase activation and involve activation of protein kinase C.
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PMID:Interactions between inhibitory and excitatory modulatory signals in single submucosal neurons. 752 97

The study of somatostatin receptors by means of autoradiography in tissue sections revealed high densities of binding sites in the immature central nervous system. In rat cerebral cortex, the receptors are present in the intermediate zone and in association with cells migrating through the cortical plate. Somatostatin receptors in the intermediate zone of fetuses and in the cortical plate of postnatal rats exhibit high and low affinities respectively for the somatostatin analogue MK 678. In the rat cerebellum, the external granule cell layer, a germinal matrix containing interneuron precursors, contains a high density of receptors. These receptors exhibit high affinity for MK 678 throughout the period of cell multiplication. In granule cell cultures from eight-day-old rats, MK 678, octreotide and somatostatin are able to inhibit cAMP formation induced by forskolin or pituitary adenylyl cyclase-activating polypeptide. Somatostatin reduces the intracellular Ca2+ concentration in cultured granule cells; this response desensitizes rapidly. These results suggest that the somatostatin receptors in the external granule cell layer are type 2 receptors (sstr2). A low density of receptors with low affinity for MK 678 was also detected in the external granule cell layer and in the granule cell layer of neonatal rats. In adult rats the cerebellum is devoid of somatostatin receptors. These observations indicate that somatostatin probably exerts morphogenetic activities through different receptor types in several structures of the central nervous system.
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PMID:Transient expression of somatostatin receptors in the brain during development. 758 43

Somatostatin induces its multiple biological actions by interacting with a family of receptors, referred to as sstr1-sstr5. To determine the molecular mechanisms of action of somatostatin, we have investigated the interaction of the different cloned receptors with G proteins and cellular effector systems. sstr2, sstr3 and sstr5 associate with pertussis toxin-sensitive G proteins and are able to mediate the inhibition of adenylyl cyclase activity by somatostatin. Two forms of sstr2, sstr2A and sstr2B, are generated by alternative splicing and differ in their C-terminal amino acid sequence. sstr2B couples to adenylyl cyclase whereas sstr2A does not. To investigate the basis for the differential coupling to adenylyl cyclase, we truncated sstr2B to the point of amino acid sequence divergence from sstr2A. The truncated sstr2B mediated the inhibition of cAMP formation by somatostatin, indicating that the C-terminus is not needed for coupling sstr2 to adenylyl cyclase. It is likely that the C-terminus of sstr2A hinders coupling to adenylyl cyclase. sstr2A associates with Gi alpha 3 and G(o) alpha but does not effectively interact with Gi alpha 1, a G protein that is necessary for coupling somatostatin receptors to adenylyl cyclase. The differential association of the splice variants with Gi alpha 1 may explain their contrasting effects on adenylyl cyclase activity. sstr3 also couples to adenylyl cyclase. Gi alpha 1 links sstr3 to adenylyl cyclase and mutagenesis studies have shown that the C-terminus of Gi alpha 1 is necessary for this coupling. The C-terminus of the Gi alpha proteins differ by only a few amino acid residues and only Gi alpha 1 couples sstr3 to adenylyl cyclase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of somatostatin receptors with G proteins and cellular effector systems. 758 45

Somatostatin regulates endocrine and exocrine secretion, possesses antiproliferative properties and acts as a neurotransmitter/neuromodulator in the central nervous system. These effects are mediated by G protein-coupled receptors, of which at least five types have been cloned (sstr1-5). In radioligand-binding studies we have compared the binding properties of sstr1-5 with their activities as somatostatin receptors. All receptors identified so far bind somatostatin-14 and somatostatin-28 with high affinity. The similarities in receptor sequence and in the binding profiles of short synthetic somatostastin analogues such as octreotide, MK 678 or RC 160 for sstr1-5 indicate the existence of two classes of receptors sstr1/sstr4 with virtually no or very low affinity and sstr2/sstr3/sstr5 with intermediate to high affinity for the short somatostatin analogues. All five receptors mediate inhibition of adenylyl cyclase; this inhibition is sensitive to pertussis toxin. In vitro and in vivo studies suggest the importance of sstr2 and/or sstr5 in the inhibition of growth hormone release. The sstr2 receptor is apparently the predominant subtype expressed in somatostatin receptor-positive tumours. Evidence exists for the importance of sstr5 receptors in insulin secretion and sstr1 receptors in oncology. Somatostatin receptor-selective agonists and antagonists will help to explore new therapeutic opportunities in oncology as well as in endocrine and gastrointestinal disorders and those of the central nervous system.
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PMID:Characterization of somatostatin receptor subtypes. 758 55

Angiopeptin (AP: BIM23014C), a cyclic analogue of the peptide hormone somatostatin, inhibits intimal hyperplasia after balloon angioplasty. This inhibition has been attributed to a direct inhibitory effect on smooth muscle cell (SMC) proliferation. However, the SMC that proliferate in the intima and contribute to intimal hyperplasia arrive there by migrating from the injured media, suggesting that SMC migration may also play an important role in this process. Indeed, in the experiments we describe, AP inhibited the migration of rat aortic SMC cells (RA-SMC) in response to type I collagen, the predominant form of collagen in the vessel media, and did so dose dependently. RA-SMC migration was inhibited 70% in the presence of AP 100 nM. RA-SMC adhesion to type I collagen in these conditions was not inhibited, suggesting that AP does not interfere with RA-SMC recognition of type I collagen; instead, it blocks subsequent signaling events that are necessary for RA-SMC migration in response to type I collagen. AP inhibited the forskolin-stimulated accumulation of cyclic AMP by RA-SMC (35% at 30 nM). In addition, pertussis toxin (PT), which blocks Gi-mediated inhibition of adenylyl cyclase, blocked the inhibitory effect of AP on cyclic AMP (cAMP) accumulation and also blocked the inhibitory effect of AP on RA-SMC migration. These findings suggest that the inhibitory effect of AP on intimal hyperplasia is due at least in part to its effects on SMC migration and that these effects are mediated by a Gi-dependent pathway and may involve inhibition of adenylyl cyclase and cAMP accumulation.
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PMID:Angiopeptin (BIM23014C) inhibits vascular smooth muscle cell migration in vitro through a G-protein-mediated pathway and is associated with inhibition of adenylyl cyclase and cyclic AMP accumulation. 759 30

The present study examined the effects of histamine on somatostatin-like immunoreactivity levels, binding of 125I-[Tyr11]somatostatin to its specific receptors, somatostatin inhibition of basal and forskolin-stimulated adenylyl cyclase activity and inhibitory guanine-nucleotide binding protein (Gi) function in the rat frontoparietal cortex. An intracerebroventricular (i.c.v.) dose of 10 micrograms or 1 microgram of histamine induced an increase in the number of specific 125I-[Tyr11]somatostatin receptors (590 +/- 22 vs 358 +/- 12 fmol/mg protein, P < 0.001 and 455 +/- 20 vs. 342 +/- 21 fmol/mg protein, P < 0.01, respectively) together with a decrease in their apparent affinity (0.76 +/- 0.04 vs 0.39 +/- 0.02 nM, P < 0.001 and 0.60 +/- 0.03 vs 0.39 +/- 0.05 nM, P < 0.01, respectively) in rat frontoparietal cortex membranes. This increase in tracer binding was not due to a direct effect of histamine on the somatostatin receptors since no change in binding was produced when histamine was added directly to the incubation medium. No significant differences were seen for either the basal or forskolin-stimulated adenylyl cyclase activity in frontoparietal cortex membranes of histamine-treated rats as compared with the control group. In rats treated with 10 micrograms of histamine, however, somatostatin caused a significantly greater inhibition of basal and forskolin-stimulated adenylyl cyclase activity as compared to the control group (33 +/- 4% vs 19 +/- 1% inhibition, P < 0.05 and 31 +/- 1% vs 21 +/- 3% inhibition, P < 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Exogenous histamine increases the somatostatin receptor/effector system in the rat frontoparietal cortex. 762 10


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