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

In vitro exposure of rat cerebrocortical slices to microM concentrations of serotonin (5HT) results in an increased response of adenylate cyclase to isoproterenol (ISO). No change in the affinity of the beta-adrenoceptor toward the agonist was found after 5HT exposure when measuring ISO displacement of [3H]CGP 12177 binding. A similar increase of adenylate cyclase response was also found when using VIP as a stimulatory agent. The dose-response curve of adenylate cyclase to the GTP analogue, GppNHp, was modified by 5HT, which promotes a significantly higher maximal response without altering the potency of GppNHp. Forskolin-stimulated adenylate cyclase activity was not affected by 5HT. Serotonergic 5HT2 receptors are involved in the sensitization of adenylate cyclase to GppNHp, since the selective 5HT2 antagonist ketanserin inhibits the effect of 5HT, whereas the 5HT2 agonist DOI mimics 5HT. The involvement of 5HT2 receptor-coupled activation of protein kinase C is also demonstrated: direct protein kinase C activators such as phorbol esters and s,n-dioctanoylglycerol behave in the same manner as 5HT, while the protein kinase C inhibitor CGP 41251 prevents 5HT from increasing adenylate cyclase responsiveness to GppNHp. Moreover, in vitro exposure of cortical slices to 5HT results in reduced inhibition of adenylate cyclase by somatostatin. Since no change was observed at the receptor level and in the direct stimulation of the catalytic subunit of the enzyme, we propose that 5HT might accomplish the sensitization of adenylate cyclase through protein kinase C by inactivating the inhibitory coupling protein Gi and facilitating the interaction of the exogenous GppNHp with the stimulatory coupling protein Gs.
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PMID:Heterologous sensitization of adenylate cyclase activity by serotonin in the rat cerebral cortex. 790 77

The interactions of glucagon-like peptide-I(7-37)/(7-36)amide (GLP-I) and somatostatin-14 were characterized on the cyclic adenosine monophosphate (cAMP)-dependent signal transduction pathway and on proinsulin gene expression using mouse insulinoma beta TC-1 cells. GLP-I stimulated the activity of adenylate cyclase maximally at 1 mumol/L (151%). This effect was inhibited by 1 mumol/L somatostatin (119%). Forskolin also stimulated adenylate cyclase activity (10 mumol/L forskolin, 265%), and this action was inhibited by somatostatin (220%). Somatostatin alone left the basal adenylate cyclase activity unaltered. Somatostatin reduced the GLP-I-stimulated increase of intracellular cAMP levels (100 nmol/L GLP-I, 141%; 100 nmol/L GLP-I + 1 mumol/L somatostatin, 110%). GLP-I stimulated concentration-dependently the activity of protein kinase A (PKA), with a maximum at 10 nmol/L (181%). This action was inhibited by 100 nmol/L somatostatin (118%), but somatostatin did not influence the basal PKA activity. Furthermore, somatostatin reduced the GLP-I-induced stimulation of proinsulin gene expression (10 nmol/L GLP-I, 176%; 10 nmol/L GLP-I + 1 mumol/L somatostatin, 77%). Somatostatin itself inhibited concentration-dependently proinsulin gene expression (1 mumol/L somatostatin, 53%). These data demonstrate that GLP-I increases the activities of both adenylate cyclase and cAMP-dependent PKA, whereas somatostatin counteracts the stimulatory effect of GLP-I on adenylate cyclase activity, cAMP generation, PKA activity, and proinsulin gene expression. The interaction of both hormones occurs at the level of adenylate cyclase. Therefore, the interaction of both peptide hormones regulates downstream events, including gene expression.
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PMID:Interaction of glucagon-like peptide-I (7-37) and somatostatin-14 on signal transduction and proinsulin gene expression in beta TC-1 cells. 791 Dec 22

The regulation and function of CREB was examined in B cells to begin to elucidate the role of cAMP-derived signals in B cell activation. CRE-binding activity detected by the electrophoretic mobility shift assay was found to be constitutively expressed in nuclear extracts of primary murine splenic B cells and was unchanged in nuclear extracts obtained from B cells stimulated in a variety of ways. This activity was shown to be specific by competition analysis and to represent CREB or a closely related molecule on the basis of a "supershift" in the mobility of the nucleoprotein complex induced by anti-CREB antiserum. The function of B cell CREB was assessed by transient transfection of the murine B lymphoma cell line, BAL-17, with a CRE-dependent chloramphenicol acetyl-transferase (CAT) construct that contains a portion of the somatostatin promoter. Cross-linking of the surface Ig receptors of transfected BAL-17 B cells produced a threefold induction of CAT activity. Forskolin, which markedly induced CAT expression in PC12 cells transfected with the CRE-dependent construct, failed to stimulate CAT activity in transfected BAL-17 B cells despite an increase in cAMP. However, anti-Ig was found to act in synergy with forskolin to produce enhanced CAT activity. A phosphoprotein of appropriate molecular size for CREB was immunoprecipitated from anti-Ig plus forskolin treated BAL-17 B cells. These results suggest that CREB is present in primary B cells and that CRE-dependent gene expression is regulated by surface Ig either alone or in synergy with cAMP; the latter implies cross-talk between intracellular signaling pathways acting at the level of CREB.
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PMID:Induction of CREB activity via the surface Ig receptor of B cells. 839 39

The aim of this study was to examine the potencies of several recently identified selective somatostatin (SRIF)-receptor ligands as inhibitors of electrogenic ion transport in the rat distal colonic mucosa with the view to identifying the SRIF receptor type involved. Under basal conditions, cumulative administration of SRIF and SRIF28 decreased short circuit current (SCC), a measure of electrogenic ion transport, with EC50 values of 4 nM and 9 nM respectively. The peptidase inhibitors, phosphoramidon (1 microM) and amastatin (10 microM), has no effect on the potencies of either SRIF or SRIF28. The inhibitory action of SRIF on basal SCC was suppressed by piretanide and diphenylamine-2-carboxylate, compatible with the assumption that the Na+K+2Cl- co-transporter and Cl- channels, respectively, may be involved in this antisecretory action of SRIF. Tetrodotoxin (1 microM) had no effect on the antisecretory action of SRIF, suggesting that the process was not neuronally mediated. All of the SRIF analogues examined, with the exception of BIM-23056, maximally inhibited basal SCC to a similar extent as SRIF. Seglitide and octreotide were both more potent antisecretory agents than SRIF (respective EC50 values, 0.4 nM and 1.5 nM) suggesting that this effect was mediated by a receptor belonging to the SRIF1 receptor group. The most distinguishing feature of the rank order of agonist potencies was the high potency of the selective sst2 receptor ligand, BIM-23027 (EC50 value 0.32 nM), the weaker potency exhibited by the selective sst5 receptor ligand, L-362855 (EC50 value 21 nM), and the lack of agonist activity displayed by the selective sst3 receptor ligand, BIM-23056 (EC50 value > 1000 nM). This profile is comparable with that observed in binding studies on the recombinant sst2 receptor. Forskolin-stimulated secretion was suppressed by SRIF analogues with the rank order of agonist potencies BIM-23027 > SRIF > L-362855 >> BIM-23056 which resembled that exhibited under basal conditions. However, the absolute potencies of these agonists were lower (respective EC50 values 2 nM, 14 nM< 38 nM and > 1000 nM) whilst the magnitude of inhibition was about three fold greater. BIM-23027 and SRIF (both 30 nM) also inhibited carbachol-stimulated increases in basal SCC by 60-70%, while a similar concentration of L-362855 inhibited these responses by 11%. BIM-23056 (1 microM) had no effect on carbachol-simulated secretion. Radioligand binding studies on rat colonic mucosal membranes using [125I]-Tyr11-SRIF suggested heterogeneity of SRIF binding sites. Thus, SRIF and SRIF28 competed for binding (IC50 values, 0.32 and 0.63 nM, respectively) with Hill slopes less than unity; while seglitide and BIM-23027 both maximally displaced only 30-40% of specific binding with apparent high affinity (respective pIC50 values, 10.1 nM and 10.0). In conclusion, SRIF decreases basal as well as both cAMP and Ca(2+)-dependent Cl- secretion in rat colonic mucosa. The rank order of agonist potencies suggests that receptors resembling the recombinant sst2 receptor mediate inhibition of basal and forskolin-stimulated secretion. Radioligand binding studies suggest that BIM-23027 interacts with a sub-population of [125I]Tyr11-SRIF binding sites in rat colonic mucosal membranes which probably corresponds to the receptors mediating the antisecretory effects described here.
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PMID:Somatostatin receptors mediating inhibition of basal and stimulated electrogenic ion transport in rat isolated distal colonic mucosa. 853 68

Effector coupling of somatostatin receptor subtypes sst1 and sst2 was examined in a reconstituted system. Forskolin-stimulated cyclic adenosine monophosphate (cAMP) formation was inhibited 66% by somatostatin (SRIF-14) in CHO cells expressing somatostatin receptor 1(sst1) (CHO-SR1), but not sst2, in a dose-dependent manner with an ED50 of 1 x 10(-9) mol/L SRIF-14. The inhibition was blocked by pertussis toxin (PTX), indicating that sst1 is coupled to adenylyl cyclase via PTX-sensitive Gi protein. In CHO cells, Gi alpha 2 and Gi alpha 3 mRNAs were detected. In adenylyl cyclase assays, 1 mumol/L SRIF-14 caused a 16% inhibition of forskolin-stimulated adenyly cyclase activity. Preincubation with Gi alpha 3, but not Gi alpha 1/Gi alpha 2, antiserum blocked this inhibition. By contrast, sst2 is coupled to adenylyl cyclase via Gi alpha 1. In cells expressing sst2 with Gi alpha 1(CHO-SR2G1), SRIF-14 significantly inhibited forskolin-stimulated cAMP formation by 53% and with an ED50 at 4 x 10(-9)mmol/L SRIF-14, which was completely blocked by PTX; ED50 values for sst1 and sst2 agree with the IC50 values in binding assays. In CHO-SR1, the rank of potency of agonists affecting adenyl cyclase was SRIF-14 = SRIF-28 > RC 160 > SMS 201-995. In CHO-SR2G1, the rank was RC-160 > SRIF-14 = SRIF-28 > SMS 201-995.
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PMID:Effector coupling of somatostatin receptor subtypes on human endocrine tumors. 876 78

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

The release of somatostatin-like immunoreactivity was studied in isolated synaptosomes. A significant release of somatostatin-like immunoreactivity was observed in the presence of vasoactive intestinal polypeptide (VIP) (10(-6) M: 53.0 +/- 12.4 pg/mg, basal: 14.3 +/- 1.7 pg/mg, n = 5, P < 0.05), secretin (10(-6) M: 56.1 +/- 3.8 pg/mg, basal: 25.8 +/- 1.6 pg/mg, n = 6, P < 0.01) and isoproterenol (10(-5) M: 54.0 +/- 13.4 pg/mg, basal: 20.0 +/- 3.4 pg/mg, n = 8, P < 0.05). Forskolin, an unspecified activator of the adenylate cyclase, caused a significant release of somatostatin-like immunoreactivity (10(-6) M: 57.3 +/- 13.2 pg/mg, basal: 30.0 +/- 5.8 pg/mg, n = 13, P < 0.01) which was further augmented in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX 10(-4) M) (77.0 +/- 17.8 pg/mg, n = 13, P < 0.01). 3-Isobutyl-l-methylxanthine and N6, 2'-O-dibutyryladenosine-3',5'-cyclic monophosphate mimicked at effect of forskolin and VIP. The release of somatostatin was paralleled by an increase of cAMP immunoreactivity in the presence of VIP (10(-6) M: 37.1 +/- 9.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.05), isoproterenol (10(-5) M: 42.4 +/- 9.8 pmol/mg basal: 16.7 +/- 2.4 pmol/mg, n = 12, P < 0.01) and forskolin (10(-6) M: 47.1 +/- 12.4 pmol/mg, basal: 19.8 +/- 4.2 pmol/mg, n = 10, P < 0.01). The effect of nitric oxide (NO) which acts as an inhibitory neurotransmitter in the enteric nervous system was studied. NO is known to activate guanylate cyclase to induce transmitter release. The NO-generating compound sodium nitroprusside and bromoguanosine-3',5'-cyclic monophosphate (8-Br-cGMP) had no effect on the release of somatostatin-like immunoreactivity. These data demonstrate the stimulatory effect of VIP, secretin and isoproterenol on release of somatostatin-like immunoreactivity from enteric synaptosomes, which is presumably mediated by cAMP-dependent mechanisms. cGMP-dependent mechanisms seem to be of minor relevance.
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PMID:Presynaptic modulation by VIP, secretin and isoproterenol of somatostatin release from enriched enteric synaptosomes: role of cAMP. 895 33

Repeated stimulation of pituitary cell cultures with GH-releasing hormone (GHRH) results in diminished responsiveness, a phenomenon referred to as homologous desensitization. One component of GHRH-induced desensitization is a reduction in GHRH-binding sites, which is reflected by the decreased ability of GHRH to stimulate a rise in intracellular cAMP. In the present study, we sought to determine if homologous down-regulation of GHRH receptor number is due to a decrease in GHRH receptor synthesis. To this end, we developed and validated a quantitative RT-PCR assay system that was capable of assessing differences in GHRH-R messenger RNA (mRNA) levels in total RNA samples obtained from rat pituitary cell cultures. Treatment of pituitary cells with GHRH, for as little as 4 h, resulted in a dose-dependent decrease in GHRH-R mRNA levels. The maximum effect was observed with 0.1 and 1 nM GHRH, which reduced GHRH-R mRNA levels to 49 +/- 4% (mean +/- SEM) and 54 +/- 11% of control values, respectively (n = three separate experiments; P < 0.05). Accompanying the decline in GHRH-R mRNA levels was a rise in GH release; reaching 320 +/- 31% of control values (P < 0.01). Because of the possibility that the rise in medium GH level is the primary regulator of GHRH-R mRNA, we pretreated pituitary cultures for 4 h with GH to achieve a concentration comparable with that induced by a maximal stimulation with GHRH (8 micrograms GH/ml medium). Following pretreatment, cultures were stimulated for 15 min with GHRH and intracellular cAMP accumulation was measured by RIA. GH pretreatment did not impair the ability of GHRH to induce a rise in cAMP concentrations. However, as anticipated, GHRH pretreatment (10 nM) significantly reduced subsequent GHRH-stimulated cAMP to 46% of untreated controls. These data suggest that GHRH, but not GH, directly reduces GHRH-R mRNA levels. To determine whether this effect was mediated through cAMP, cultures were treated with forskolin, a direct stimulator of adenylate cyclase. Forskolin (10 microM) significantly reduced GHRH-R mRNA concentrations (37 +/- 6% of control values) indicating that GHRH acts through the cAMP-second messenger system cascade to regulate GHRH-R mRNA. The somatostatin analogue, octreotide (10 nM), which has been previously reported to decrease adenylate cyclase activity, did not affect GHRH-R mRNA levels. Taken together, these results indicate that GHRH inhibits the production of its own receptor by a receptor-mediated, cAMP-dependent reduction of GHRH-R mRNA accumulation.
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PMID:Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels. 904 9

Angiopeptin, a stable octapeptide analog of somatostatin, inhibits proliferation in a variety of cancer cell lines. We studied the effect of angiopeptin on 3H-thymidine uptake into ring segments from the porcine coronary tree. The incorporation of 3H-thymidine into segments of porcine left anterior descending (LAD) coronary artery was time dependent and reached a plateau after 48 h. The addition of angiopeptin (48.1 and 96.2 nM) to the culture medium significantly inhibited 3H-thymidine incorporation into the segments by 36.7 +/- 10.1% and 48.3 +/- 2.3% of the control, respectively. Forskolin (100 microM), inhibited 3H-thymidine incorporation (52.7 +/- 10.1%) to the same degree as did angiopeptin (96.2 nM). Incubation of the segments with 125I-labeled angiopeptin, for 2 h at 37 degrees C, showed angiopeptin uptake to be time dependent and exhibited a first-order kinetics, reaching equilibrium after 30 min. Autoradiographic studies showed a uniform distribution of angiopeptin within the endothelium, media, and adventitia. Most of the labeling was associated with the nuclei of the cells. Angiopeptin, after 30-min incubation, did not significantly modify the basal levels of cyclic adenosine monophosphate (cAMP). In contrast, forskolin (100 microM) elicited a 50-fold increase of the basal levels of cAMP. These results indicate that in addition to its endocrine effects, angiopeptin reduces the rate of proliferation by acting directly on the vessel wall.
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PMID:Angiopeptin inhibits thymidine incorporation by explants of porcine coronary arteries. 905 79

We conducted this study to investigate the mechanisms of action of growth hormone-releasing peptide-2 (D-Ala-D-beta Nal-Ala-Trp-D-Phe-Lys-NH2; GHRP-2) in bovine anterior pituitary primary cell culture. Doses of GHRP-2 from 10(-13) to 10(-7) M) increased (P < .05) GH secretion. The GHRP-2 (10(-7) M) and GH-releasing factor (GRF; 10(-7) M) administered together had an additive effect on the release of GH (P < .05). Somatostatin (1 microM) decreased GH secretion in response to GHRP-2 and(or) GRF (P < .05). Secretion of GH in response to GHRP-2 was blocked (P < .01) by a GRF receptor antagonist (.1 microM). Nifedipine (10 microM), a voltage-dependent Ca2+ channel blocker, inhibited (P < .01) GHRP-2-stimulated GH release. The GH release in response to GHRP-2 and 4 beta-phorbol-12-myristate-13-acetate (10(-7) M), a protein kinase C activator, was additive (P < .01). Forskolin (30 microM), a cAMP elevating agent, further stimulated (P < .01) the GH release in response to GHRP-2. Bovine GH concentrations in culture media were assayed by indirect competitive enzyme immunoassay. These results showed that GHRP-2 1) stimulates GH secretion from bovine pituitary cells, 2) may partially act via GRF receptor, 3) has GH secretion activity caused by Ca2+ influx via Ca2+ channels, and 4) may increase GH secretion via protein kinase C and cAMP pathways.
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PMID:Mechanisms of action of growth hormone-releasing peptide-2 in bovine pituitary cells. 933 79


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