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 effects of somatostatin on insulin release and cyclic AMP metabolism were studied in collagenase-isolated islets of Langerhans from the rat. Ceoncentrations from 500 to 2000 ng/ml significantly inhibited glucose stimulated insulin release, while 100 and 200 ng/ml were ineffective. Somatostatin (2000 ng/ml) inhibited insulin release and [3H]-cyclic AMP accumulation induced by 16.7 mM glucose after 10 and 30 min of incubation. In dose-response studies, the inhibition by somatostatin of the effect of glucose on [3H]cyclic AMP and insulin release could be overcome by a high concentration of the hexose (44.9 mM), suggesting competitive inhibition. In the absence of glucose, somatostatin inhibited [3H]cyclic AMP accumulation induced by the phosphodiesterase inhibitor, IBMX, while no inhibition was seen, again in the absence of hexose, when the [3H]cyclic AMP levels had been raised by the adenyl cyclase stimulator, cholera toxin. Somatostatin did not affect phosphodiesterase activity when added to islet homogenates, but preincubation of the islets with the peptide before homogenization decreased the activity by about 30%. It is suggested that somatostatin-induced inhibition of insulin release is, at least partially, mediated by cyclic AMP, probably through an action on islet adenyl cyclase.
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PMID:Studies on the mechanisms of somatostatin action on insulin release. IV. effect of somatostatin on cyclic AMP levels and phosphodiesterase activity in isolated rat pancreatic islets. 19 42

The effects of endogenous hypothalamic neurohormones and activators of second messenger signalling systems on the secretion of GH and on cell content of GH mRNA of cultured bovine adenohypophysial cells were studied. Synthetic bovine GH-releasing factor (bGRF; 100 nmol/l) increased secretion of GH by bovine adenohypophysial cells five-fold relative to control. Forskolin (an adenyl cyclase activator; 10 mumol/l) and the synthetic cyclic AMP analogue dibutyryl cyclic AMP (dbcAMP; 1 mmol/l) increased secretion of GH by 1.9- and 1.7-fold respectively, relative to control. The protein kinase C activator phorbol 12-myristate 13-acetate (PMA), provided at 1 mumol/l or 10 nmol/l, increased GH secretion by 6.6- and four-fold respectively, relative to control. Somatostatin-14 (SRIF-14) attenuated basal, bGRF-, forskolin- and dbcAMP-stimulated secretion of GH by 40, 49, 47 and 67% respectively, but did not, however, diminish PMA-stimulated GH secretion. The content of GH mRNA in cultured bovine adenohypophysial cells increased 2.2-, 1.7- and 3.2-fold by administration of bGRF, forskolin and PMA respectively, relative to control. Although GH mRNA content was unchanged by SRIF-14 treatment relative to control, SRIF-14 did reduce bGRF-stimulated bGH mRNA content by 67%. This study demonstrates that mechanisms subserving GH secretion in bovine adenohypophysial cells (e.g. adenyl cyclase and protein kinase C) may be coupled with mechanisms which regulate expression of the GH gene or with factors affecting message stability.
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PMID:Modulation of growth hormone (GH) secretion and GH mRNA levels by GH-releasing factor, somatostatin and secretagogues in cultured bovine adenohypophysial cells. 197 Oct 2

Regulation of GH gene expression by GRF involves cAMP as a second messenger. We have demonstrated that a 500-basepair fragment of the human GH (hGH) gene 5' flanking region can confer cAMP inducibility upon the chloramphenicol acetyltransferase transcription unit in transient transfections of rat pituitary tumor cells treated with forskolin, an activator of adenyl cyclase. The same hGH construct is not induced by forskolin in nonpituitary-derived cells. Experiments with hGH deletion constructs reveal that binding sites for transcription factor AP-2 and the pituitary-specific factor GHF-1 are not required for forskolin stimulation, but that GHF-1 may potentiate the effect. RNA analyses reveal that forskolin also stimulates accumulation of transcripts initiated at the hGH promoter. Other agents that elevate cAMP levels also stimulate hGH expression. Since the hGH 5' flanking region contains no sequences homologous to the cAMP-responsive element of the somatostatin gene, and the AP-2 sites do not appear to be required for the forskolin response, these results suggest that a novel cAMP-responsive element exists within 82 basepairs upstream from the transcriptional start of the hGH gene and that hGH regulation by GRF may involve interaction between a tissue-specific element and a cAMP-inducible element.
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PMID:Induction of human growth hormone promoter activity by the adenosine 3',5'-monophosphate pathway involves a novel responsive element. 254 55

A recently developed primary cell-culture system allows direct study of the cellular mechanisms regulating neurotensin secretion from intestinal mucosal cells. We now report the use of these methods to evaluate the modulation of neurotensin release by adrenergic, cholinergic, and peptidergic transmitters. Collagenase-dispersed canine ileal mucosal cells, enriched for neurotensinlike immunoreactivity (NTLI) by centrifugal elutriation, were maintained for 48 h on collagen-coated culture dishes. Epinephrine (0.01-100 microM) stimulated a dose-dependent increase increase in NTLI secretion. The NTLI response to epinephrine increase in NTLI secretion. The NTLI response to epinephrine was competitively inhibited by propranolol, producing a parallel rightward shift of the epinephrine dose-response curve. alpha-Adrenergic agonist methoxamine (10 microM) and clonidine (10 microM) did not alter basal NTLI secretion. Epinephrine stimulation was not significantly inhibited by the alpha-adrenergic antagonists prazosin (10 microM) or yohimbine (10 microM). The diterpene forskolin, an adenyl cyclase activator, increased NTLI release and had an additive effect on the response to epinephrine. In contrast to beta-adrenergic activation, carbachol and somatostatin produced a dose-dependent inhibition of epinephrine-stimulated NTLI release. At 100 microM carbachol, NTLI release was inhibited 68%, and this action was partially blocked by atropine (0.1 microM). Somatostatin (100 nM) produced a 96% inhibition that was not surmountable by 1 mM epinephrine. These data indicate that neurotensin release is stimulated by beta-adrenergic agonists and adenylate cyclase activation. Somatostatin and the muscarinic agonist carbachol directly inhibit NTLI release.
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PMID:Regulation of neurotensin release from canine enteric primary cell cultures. 286 96

Many hormones act on neuroendocrine cells by activating second messenger pathways. Two of these, the phosphoinositol and cAMP-dependent pathways, cause changes in cellular activity through specific protein kinases. By phosphorylating cytoplasmic and nuclear proteins, these kinases apparently coordinate cellular processes, including the biosynthesis and release of neuropeptides. Somatostatin biosynthesis and release, for example, are both positively regulated by the second messenger cAMP in hypothalamic cells, and cAMP also induces somatostatin gene transcription 8-10-fold in transfected PC12 pheochromocytoma cells. Transcriptional induction requires a 30-nucleotide cAMP response element (CRE) which is conserved in other cAMP-responsive genes. This element also confers cAMP responsiveness when placed upstream of the heterologous simian virus 40 (SV40) promoter. The somatostatin gene does not, however, respond to cAMP in mutant PC12 cells which lack cAMP-dependent protein kinase type II activity. Activation of somatostatin gene transcription may consequently require the phosphorylation of a nuclear protein which binds to the CRE. Using a DNase I protection assay, we have characterized a nuclear protein in PC12 cells which binds selectively to the CRE in the somatostatin gene. We have purified this protein which is of relative molecular mass 43,000 (Mr 43K) by sequence-specific DNA affinity chromatography. This 43K CRE binding protein (CREB) is phosphorylated in vitro when it is incubated with the catalytic subunit of cAMP-dependent protein kinase. Stimulating PC12 cells with forskolin, an activator of adenyl cyclase, causes a 3-4-fold increase in the phosphorylation of this protein. We conclude that the cAMP-dependent pathway may regulate gene transcription in response to hormonal stimulation by phosphorylating this CREB protein.
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PMID:Binding of a nuclear protein to the cyclic-AMP response element of the somatostatin gene. 288 56

Enteroglucagon-containing cells have been maintained in short-term culture, and the morphologic characteristics of these cells and their response to selected agents have been determined. After 48 h in culture the ultrastructural appearance of the enteroglucagon-immunoreactive cells showed evidence of polarization with re-formation of apical microvilli and the secretory granules concentrated at the opposite pole of the cell. The size of the intracellular secretory granules was 370 +/- 15 nm. The release of enteroglucagonlike immunoreactivity was stimulated in a dose-dependent manner by the adrenergic agonists epinephrine and isoproterenol. The response to epinephrine was competitively inhibited by propranolol, producing a rightward shift of the dose-responsive curve. The alpha-adrenergic agonists methoxamine and clonidine did not stimulate enteroglucagon release above basal. The adenyl cyclase activator forskolin also stimulated release of the peptide in a dose-dependent manner. Carbachol and somatostatin produced a dose-dependent inhibition of epinephrine-stimulated release, indicating direct inhibitory modulation of enteroglucagonlike immunoreactive cells. Somatostatin also inhibited forskolin-stimulated release. These data indicate that canine ileal enteroglucagon cells in short-term culture respond to a number of specific stimuli.
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PMID:Morphologic and physiologic studies of canine ileal enteroglucagon-containing cells in short-term culture. 288 80

Isolated elements of the beta-adrenergic/adenyl cyclase signal transduction system have been studied previously using purified membranes. We used cultured syncytiotrophoblast cells to identify components of this signalling system and the interactions which regulate syncytial adenyl cyclase. Generation of cyclic AMP (cAMP) was stimulated in these cells by both forskolin and isoproterenol but not by dopamine, adenosine, carbachol or prostaglandin E1. Synthesis was also stimulated by treatment with cholera toxin, indicating the involvement of the G-protein, Gs. Somatostatin inhibited isoproterenol- or forskolin-stimulated cAMP generation, an effect which could be blocked by pretreatment of the cells with pertussis toxin, demonstrating the mediation of somatostatin action by Gi. Furthermore, secretion of human chorionic gonadotrophin (hCG) was increased significantly by isoproterenol while somatostatin blocked the isoproterenol-stimulated release of hCG. These results clearly demonstrate that adenyl cyclase in syncytiotrophoblast is controlled by a stimulatory pathway operating through Gs and inhibitory pathway acting through Gi.
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PMID:Beta-adrenergic regulation of cyclic AMP synthesis in cultured human syncytiotrophoblast. 857 58

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

Bicarbonate excretion in bile is a major function of the biliary epithelium. It is driven by the apically located Cl-/HCO3- exchanger which is functionally coupled with a cAMP-dependent Cl- channel (CFTR). A number of hormones and/or neuropeptides with different mechanisms and at different intracellular levels regulate, in concert, the processes underlying bicarbonate excretion in the biliary epithelium. Secretin induces a bicarbonate rich choleresis by stimulating the activity of the Cl-/HCO3- exchanger by cAMP and protein kinase A mediated phosphorylation of CFTR regulatory domain. Protein phosphatase 1/2A are involved in the run-down of secretory stimulus after secretin removal. Acetylcholine potentiates secretin-choleresis by inducing a Ca(++)-calcineurin mediated "sensitization" of adenyl cyclase to secretin. Bombesin and vasoactive intestinal peptide also enhance the Cl-/HCO3- exchanger activity, but the intracellular signal transduction pathway has not yet been defined. Somatostatin and gastrin inhibit basal and/or secretin-stimulated bicarbonate excretion by down-regulating the secretin receptor and decreasing cAMP intracellular levels induced by secretin.
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PMID:Hormonal regulation of bicarbonate secretion in the biliary epithelium. 962 62

Somatostatin and its analogue octreotide have been used for two decades to treat oesophageal variceal haemorrhage. The drug was introduced because of its capacity to decrease portal venous pressure without major side effects. In clinical trials assessing the efficacy of somatostatin and long-acting analogues in arresting variceal haemorrhage, conflicting results have been obtained. Furthermore, in haemodynamic studies evaluating the effects of somatostatin and analogues in patients with cirrhosis, divergent effects were observed. The main reason for these differences is probably related to different affinities of the drugs for different somatostatin receptor subtypes. The effects of somatostatin and analogues are mediated via five different G-protein coupled receptors (somatostatin receptor subtypes 1-5), which regulate the activity of ion channels (Ca2+, K+, Na+ and Cl-) and enzymes (adenyl cyclase, phospholipase C, phospholipase A2, phosphoinositide 3-kinase and guanylate cyclase) responsible for the synthesis or degradation of intracellular second messengers including cyclic AMP, inositol 1,4,5-trisphosphate, diacylglycerol and cyclic GMP. Despite universal use of somatostatin, the cellular and biochemical mechanisms of its effects in portal hypertension are relatively poorly studied and remain incompletely understood. In this review, we summarize relevant signal transduction of somatostatin and analogues, the haemodynamic effects of the drugs and the possible mechanisms by which these effects are mediated.
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PMID:Pharmacological rationale for the use of somatostatin and analogues in portal hypertension. 1294 Sep 22


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