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)

1. The coupling of the human somatostatin sst5 receptor recombinantly expressed in Chinese hamster ovary (CHO-K1) cells to adenylate cyclase was investigated using receptor selective ligands. 2. Forskolin (10 microM)-stimulated adenosine 3': 5'-cyclic monophosphate (cyclic AMP) accumulation was inhibited by somatostatin-14 and a number of receptor-selective agonists with a rank order of agonist potency typical of the sst5 receptor. L-362,855 and BIM-23056 behaved as full agonists. At higher somatostatin-14 concentrations there was sub-maximal inhibition resulting in a bell-shaped concentration-effect relationship. Pertussis toxin (PTx; 100 ng ml(-1), 18 h) pre-treatment abolished agonist-mediated inhibition of cyclic AMP accumulation and markedly enhanced stimulation of cyclic AMP at higher agonist concentrations. 3. The concentration of prostaglandin E2 (PGE2) in the incubation media was raised 14 fold by 1 microM somatostatin-14 but was insufficient to stimulate adenylate cyclase activity via endogenous prostanoid receptors. 4. Pre-treatment with cholera toxin (ChTx; 20 microg ml(-1), 18 h) markedly inhibited sst5 receptor-mediated increases in cyclic AMP formation in intact cells. Somatostatin-14-stimulated cyclic AMP accumulation was also observed in sst5 receptor containing CHO-K1 membranes and was inhibited by the synthetic peptide Galphasacetyl-354-372-amide (100 microM) by 65.9+/-3.5%, implicating a Galphas protein involvement in this response. 5. Activation of Galphas proteins by somatostatin-14 could be demonstrated with [35S]-guanosine 5'-[gamma-thio]triphosphate ([35S]-GTPgammaS) binding and subsequent immunoprecipitation of 35S labelled Galphas proteins with anti-Galphas serum. 6. These data show that the sst5 receptor is very efficiently coupled in a negative manner to adenylate cyclase. However, at higher agonist concentrations the receptor can also mediate activation of adenylate cyclase by a mechanism apparently involving Galphas protein activation.
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PMID:Activation of adenylate cyclase by human recombinant sst5 receptors expressed in CHO-K1 cells and involvement of Galphas proteins. 1020 12

The first cloned non-mammalian somatostatin (somatostatin release-inhibiting factor = SRIF) receptor previously obtained from the teleost fish Apteronotus albifrons and generically named somatostatin receptor 3 (fsst3), was stably expressed and characterised in Chinese hamster lung fibroblast (CCL39) cells. Radioligand binding studies were performed with four radioligands selective for SRIF receptors in CCL39 cells expressing the fsst3 receptors; [125I]LTT-SRIF28 ([Leu8, D-Trp22, 125I-Tyr25]-SRIF28), [125I]Tyr10-cortistatin, [125I]CGP 23996, and [125I]Tyr3-octreotide labelled the fsst3 receptor with high affinity (pKd values: 10.47, 10.87, 9.59 and 9.57) and in a saturable manner, but defined different Bmax values; 4500, 4000, 3400 and 1500 fmol/mg, respectively. The affinities of SRIF peptides and analogues determined for fsst3 receptors displayed the following rank order of potency: seglitide = SRIF25 > SRIF14 = SRIF28 > cortistatin 14 > BIM 23014 > RC160 = L361,301 = octreotide > or = BIM 23052 > or = L362,855 > CGP23996 > BIM 23056 > BIM 23030 = cycloantagonist > SRIF22. The pharmacological profiles determined with [125I]LTT-SRIF28, [125I]CGP 23996 and [125I]Tyr10-cortistatin correlated highly significantly (r = 0.96-0.99), whereas [125I]Tyr3-octreotide binding was rather divergent (r = 0.78-0.81). Further, [125I]Tyr3-octreotide- and [125I]CGP 23996-labelled sites showed higher affinity for the various peptides than [125I]LTT-SRIF28 and [125I]Tyr10-cortistatin-labelled sites, although there were exceptions. [125I]LTT-SRIF28-binding to fsst3 receptors and human sst1-5 receptors was compared; the fsst3 binding profile correlated better with the hsst5- than with the hsst3 receptor profile. SRIF inhibited potently forskolin-stimulated adenylate cyclase activity in fsst3 transfected CCL39 cells; this effect was blocked by pertussis toxin, suggesting coupling of the fsst3 receptor to Gialpha and/or Goalpha. [125I]LTT-SRIF28 binding was detected in fish brain, liver, heart, spleen, and stomach, but not in gut. The pharmacological profile of [125I]LTT-SRIF28-labelled sites in brain, but not in liver, correlated significantly with the recombinant fsst3 receptor, in agreement with expression of the fsst3 receptor gene found by RT-PCR in the brain. However, biphasic binding curves obtained with two SRIF-analogues in brain, as well as the distinct pharmacological profile of the liver SRIF receptor, suggest the existence of several yet to be defined SRIF receptor subtypes in fish. The present data demonstrate that the recombinantly expressed fsst3 receptor has a pharmacological profile compatible with that of a SRIF1 receptor, although the rank order of affinity of fsst3 is closer to that of hsst5 than hsst3 receptors, as may be found when comparing very distantly related species. The fsst3 receptor expressed in CCL39 cells, is negatively coupled to adenylate cyclase activity via pertussis toxin-sensitive G-proteins, like mammalian sst3 receptors. Radioligand binding performed with fish tissue suggests the presence of a native sst3 receptor in brain as well as other yet to be defined SRIF receptor subtypes.
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PMID:Characterisation of the fish sst3 receptor, a member of the SRIF1 receptor family: atypical pharmacological features. 1021 83

The actions of the various forms of somatostatin (SRIF), including those of the tetradecapeptide SRIF(14), are mediated by specific receptors. In mammals, five subtypes of SRIF receptors, termed sst(1-5), have been cloned. Using a combination of reverse transcriptase-polymerase chain reaction and genomic library screening in the gymnotiform fish Apteronotus albifrons, a gene encoding the first-known nonmammalian SRIF receptor has been isolated. The deduced amino acid sequence displays 59% identity with the human sst(3) receptor protein; hence, the gene is termed "Apteronotus sst(3)." The predicted protein consists of 494 amino acid residues exhibiting a putative seven-transmembrane domain topology typical of G protein-coupled receptors. A signal corresponding to the Apteronotus sst(3) receptor was detected in brain after amplification of poly(A)(+)-RNA by reverse transcriptase-polymerase chain reaction, but not by Northern blot analysis or in situ hybridization, suggesting a low level of expression. Membranes prepared from CCL39 cells stably expressing the Apteronotus sst(3) receptor gene bound [(125)I][Leu(8),d-Trp(22), (125) I-Tyr(25)]SRIF(28) with high affinity and in a saturable manner (B(max) = 4470 fmol/mg protein; pK(D) = 10.5). SRIF(14) and various synthetic SRIF receptor agonists produced a dose-dependent inhibition of radioligand binding, with the following rank order of potency: SRIF(14) approximately SRIF(28) > BIM 23052 > octreotide > BIM 23056. Under low stringency conditions, an Apteronotus sst(3) probe hybridized to multiple DNA fragments in HindIII or EcoRI digests of A. albifrons DNA, indicating that the Apteronotus sst(3) receptor is a member of a larger family of Apteronotus SRIF receptors.
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PMID:Molecular cloning and pharmacological characterization of a somatostatin receptor subtype in the gymnotiform fish Apteronotus albifrons. 1048 Sep 84

Recently, it was demonstrated that somatostatin analogs preferential for the SSTR5 subtype suppress PRL release from prolactinoma cell cultures by 30-40%. These data supported the idea of somatostatin receptor subtype-specific control of PRL secretion in such tumors. The present study examines the quantitative profile of SSTRs messenger ribonucleic acid (mRNA) in 10 PRL-secreting tumors and correlates the expression with the ability of native somatostatins (SS14 and SS28), SSTR2 preferential analogs (octreotide and BIM-23197), and the SSTR5 preferential analog BIM-23268 to suppress PRL secretion. RT-PCR quantitative analysis showed a large predominance of SSTR5 mRNA [5648 +/- 1918 pg/pg glyceraldehyde-3-phosphate dehydrogenase (GAPDH)] vs. SSTR2 mRNA (148 +/- 83 pg/pg GAPDH). The SSTR1 transcript was also highly expressed in prolactinomas (1296 +/- 669 pg/pg GAPDH). SSTR5 mRNA expression correlated with PRL inhibition induced by both SRIF14 and SRIF28. Among the different analogs tested, only BIM-23268 produced inhibition of PRL release similar to that achieved with the native peptides. Its EC50 for PRL suppression was 0.28 +/- 0.10 nmol/L. No additive effects on PRL suppression were achieved by cotreatment of the tumor cells with SSTR2 and SSTR5 preferential analogs. In the same tumor cell cultures, quinagolide, a potent dopamine agonist, produced a dose-dependent inhibition of PRL with an EC50 at least 10 times lower than that of BIM-23268. Coincubation of quinagolide and BIM-23268, particularly in tumor cells resistant to dopamine agonist treatment, did not produce additive effects on PRL suppression. In conclusion, prolactinomas have a specific pattern of SSTR subtype mRNA expression (SSTR5 and SSTR1). SSTR5 expression is correlated to PRL regulation. These inhibitory effects are superimposable, at a higher concentration, to those of the dopamine agonists, but are not additive, particularly in the adenomas resistant to dopaminergic suppression of PRL release.
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PMID:Quantitative and functional expression of somatostatin receptor subtypes in human prolactinomas. 1048 98

The main physiological role of somatostatin (SST) is the control of hormone secretion. Recently, SST has been shown to exert antiproliferative effects on some human tumors via both direct and indirect mechanisms. We have previously found that in the human neuroblastoma cell line SY5Y the SST analogue lanreotide (BIM 23014) inhibited serum-stimulated cell proliferation and MAP kinase activity. Here, we examine the effect of SST on PDGF-induced Ras activation. We found that SST suppressed PDGF-induced Ras activation in a pertussis toxin (PTx)-independent and peroxovanadate-dependent manner. Ras-specific GTPase activating protein (GAP) activities were not altered by SST treatment. On the contrary, PDGF-induced PDGF receptor phosphorylation was decreased by SST in a PTx-independent, peroxovanadate-dependent manner, likely accounting for the SST-mediated inhibition of PDGF-induced Ras activation.
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PMID:Somatostatin inhibits PDGF-stimulated Ras activation in human neuroblastoma cells. 1050 18

1 Somatostatin (SRIF) is a cyclic tetradecapeptide present in medium-sized aspiny interneurones in the rat striatum. We have previously shown that exogenous SRIF potently stimulates striatal dopamine (DA) release via a glutamate-dependent mechanism. We now report the ability of the selective sst2 receptor agonist, BIM-23027, to mimic this effect of SRIF. 2 In vivo microdialysis studies were performed in anaesthetized male Wistar rats. In most experiments, compounds were administered by retrodialysis into the striatum for 15 min periods, 90 min and 225 min after sampling commenced, with levels of neurotransmitters being measured by HPLC with electrochemical and fluorescence detection. 3 BIM-23027 (50 and 100 nM) stimulated DA release with extracellular levels increasing by up to 18 fold. 4 Prior retrodialysis of BIM-23027 (50 nM) abolished the effects of subsequent administration of SRIF (100 nM). 5 The agonist effects of both BIM-23027 and SRIF were abolished by the selective sst2 receptor antagonist, L-Tyr8-CYN-154806 (100 nM). 6 The AMPA/kainate receptor antagonist, DNQX (100 microM), abolished the agonist effects of BIM-23027 as previously shown for SRIF. 7 This study provides evidence that the sst2 receptor mediates the potent dopamine-releasing actions observed with SRIF in the rat striatum. Dopamine release evoked by both peptides appears to be mediated indirectly via a glutamatergic pathway. Other subtype-specific somatostatin receptor ligands were unable to elicit any effects and therefore we conclude that no other somatostatin receptor types are involved in mediating the dopamine-releasing actions of SRIF in the striatum.
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PMID:Evidence that somatostatin sst2 receptors mediate striatal dopamine release. 1057 51

G protein activation by somatostatin (somatotropin release inhibiting factor, SRIF), cortistatin (CST) and analogues of these neuropeptides was investigated at human somatostatin receptor subtypes 1-5 (sst1-5) stably expressed in CCL39 Chinese hamster lung fibroblast cells by measuring agonist-stimulated [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding. [35S]GTPgammaS binding was assessed in the presence of 100 mM NaCl and 1 microM GDP, although higher Emax and/or pEC50 values may have been obtained under other conditions, but at the expense of lower absolute stimulation or signal/noise ratio. SRIF14 stimulated [35S]GTPgammaS binding to 162, 220, 148 and 266% of control levels via sst2, sst3, sst4 and sst5 receptors, respectively. At sst1 receptors, SRIF14 produced only a limited stimulation (Emax 115%). Hence sst1 receptors were not subjected to further [35S]GTPgammaS binding experiments. [35S]GTPgammaS binding assays were then performed with sst2-5 receptors. Most of the peptide analogues stimulated [35S]GTPgammaS binding in sst2-5 receptor-expressing cells. BIM 23056 behaved as an antagonist on SRIF14-induced [35S]GTPgammaS binding with an apparent pKBs of 6.33 and 5.84 at hsst3 and hsst5 receptors respectively, whereas neither agonism nor antagonism could be shown (at 1 microM) at sst2 or sst4 receptors. The effect at sst5 receptors was not surmountable and needs further investigations. The so-called "antagonist" SA, was devoid of antagonist activity at sst2 or sst3 receptors, whereas it was almost a full agonist at sst4 and sst5 receptor-mediated [35S]GTPgammaS binding. The [35S]GTPgammaS-binding profiles of hsst2-5 receptors were compared with their respective radioligand binding profiles. For sst4 and sst5 receptors, the rank order of affinity of all tested radioligands correlated highly significantly with [35S]GTPgammaS binding (r = 0.814-0.897). At sst3 receptors, [35S]GTPgammaS binding correlated somewhat less with binding profiles obtained with [125I][Tyr10]CST14 and [125I]CGP 23996 than with [125I]LTT-SRIF28 (r = 0.743, 0.757 and 0.882, respectively). At sst2 receptors, [35S]GTPgammaS binding correlated with [125I]LTT-SRIF28, [125I]CGP 23996 and [125I][Tyr3]octreotide binding profiles (r = 0.596-0.699), but not with [125I][Tyr10]CST14 binding. The present [35S]GTPgammaS binding data combined to previous radioligand binding results obtained in cells expressing human SRIF receptors, suggest that at any given receptor, agonists' rank orders of potency (not to mention absolute affinity values which vary profoundly) are not as strictly ordered as may be anticipated. We are investigating these aspects further by analysing additional signalling pathways.
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PMID:Characterisation of human recombinant somatostatin receptors. 2. Modulation of GTPgammaS binding. 1059 89

The five human somatostatin receptor subtypes (hsst1-5) were stably expressed in CCL39 cells (Chinese hamster lung fibroblast cells) to study the inhibition of forskolin-stimulated adenylate cyclase (FSAC) activity induced by somatostatin (somatotropin release inhibiting factor, SRIF), cortistatin (CST) and SRIF peptide analogues. Inhibition of FSAC was observed with all five receptors, although the maximal effects produced by SRIF14 varied from around 40% (sst1, sst2, sst4) to 67% (sst3, sst5) reflecting to some extent differences in receptor density (Bmax values published in accompanying paper, this journal). SRIF28 was slightly more potent than SRIF14 to inhibit FSAC at all five receptors, although the potency of the natural peptides SRIF14, SRIF28 and CST17 was generally similar with pEC50-values ranging from 7.5 to 8.7 depending on receptor and peptide. At SRIF1 receptors (sst2, sst3, sst5) most of the peptide analogues displayed full agonism (with some exceptions e.g. BIM 23056 at sst1-3 and sst5 receptors, and L362,855 and cycloantagonist SA at sst3 receptors), whereas at SRIF2 receptors these analogues tended to behave as partial agonists. BIM 23056 was an antagonist at sst3 receptors (antagonist binding constant pKB = 6.33), but not at other receptors. The AC inhibition profiles of sst1-5 receptors were compared with the different radioligand binding profiles as well as with [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding profile for sst2-5 receptors. High correlations were observed between FSAC inhibition, radioligand binding and [35S]GTPgammaS binding profiles at sst3, sst4 and sst5 receptors; by contrast, correlation coefficients at sst1 and sst2 receptors were low, and the binding profiles of [125I][Tyr10]CST14 correlated poorly. In line with these findings, the FSAC inhibition and [35S]GTPgammaS binding correlated poorly at sst2 receptors (sst1 receptors show no significant induction of [35S]GTPgammaS binding). The apparent lack of, or only weak, relationship between FSAC, radioligand or [35S]GTPgammaS binding observed for some SRIF receptors suggests that different active states may exist for these receptors, which may favour one transduction cascade over others.
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PMID:Characterisation of human recombinant somatostatin receptors. 3. Modulation of adenylate cyclase activity. 1059 90

Total [3H]phosphoinositide (IPx) accumulation, a measure of phospholipase C (PLC) activity, induced by somatostatin (somatotropin release-inhibiting factor, SRIF) and cortistatin (CST) analogues was studied at human somatostatin receptor subtypes 1-5 (hsst1-5) recombinantly expressed in CCL39 (Chinese hamster lung fibroblast) cells. SRIF14 (10 microM) stimulated total [3H]-IPx production 200% and 1070% over basal levels, and increased intracellular Ca2+ ([Ca2+]i) 1600% and 2790%, in cells expressing hsst3 and hsst5 receptors, respectively. The SRIF14-stimulated IPx production was partly blocked by 100 ng/ml pertussis toxin (PTX) (30% and 15% inhibition, respectively). At hsst1, hsst2, and hsst4 receptors, only weak or no stimulation of PLC activity was found (Emax = 114%, 122%, and 102%, respectively). Consequently, hsst3 and hsst5 receptors were subjected to more detailed studies to establish pharmacological profiles of PLC stimulation. At hsst3 receptors, the relative efficacies of most ligands were in the same range (maximum response Emax = 218-267%). At hsst5 receptors Emax varied over a broad range, seglitide, CST17, SRIF28 displaying almost full agonism compared to SRIF14, whereas octreotide and BIM 23052 showed very low partial agonism. BIM 23056 behaved as an antagonist on SRIF14-induced total [3H]-IPx accumulation with a pKB (negative logarithm of antagonist binding constant) of 6.74 at hsst3 receptors, and of 6.94 at hsst5 receptors. The putative cycloantagonist SA showed weak antagonist activity on SRIF14-induced total [3H]-IPx levels at hsst3 (pKB = 5.85), but not at hsst5 receptors. The [3H]-IPx accumulation profiles at sst3/sst5 receptors were compared to their respective radioligand binding ([125I]LTT-SRIF28, [125I][Tyr10]CST14, [125I]CGP 23996, [125I][Tyr3]octreotide binding), to [35S]GTPgammaS binding, and to forskolin-stimulated adenylate cyclase (FSAC) inhibition profiles determined previously in CCL39 cells. The different affinity profiles correlated relatively well at both receptor subtypes with PLC activation (sst3: r = 0.90-0.97; sst5: r = 0.80-0.87). However, [35S]GTPgammaS binding correlated only minimally with stimulation of [3H]-IPx levels at sst5 receptors (r = 0.59), but rather well at sst3 receptors (r = 0.80). A moderate correlation was also observed between inhibition of FSAC activity and stimulation of PLC activity for hsst3 and hsst5 receptors with correlation coefficients of 0.85 and 0.70, respectively. In summary, most SRIF analogues behave as full agonists at hsst3 receptors and agonist-induced phosphoinositide turnover correlates well with radioligand binding, [35S]GTPgammaS binding and inhibition of adenylate cyclase activity, all measured in CCL39 cells. By contrast, at hsst5 receptors, most SRIF analogues behave as intermediate or very low partial agonists (although receptor levels are comparatively high, 7000 vs. 400 fmol/mg), and the agonist-induced phosphoinositide turnover correlates rather poorly with radioligand binding, [35S]GTPgammaS binding or inhibition of adenylate cyclase activity, all measured in the same cell line. Agonist-induced phosphoinositide turnover, [35S]GTPgammaS binding and inhibition of adenylate cyclase activity, show differences both in the rank orders of potency and relative efficacy at hsst3 and markedly at hsst5 receptors, suggesting either that PLC activity is functionally irrelevant or, more probably, that agonist-dependent receptor trafficking is taking place in CCL39 cells.
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PMID:Characterisation of human recombinant somatostatin receptors. 4. Modulation of phospholipase C activity. 1059 91

Recently, studies using somatostatin (SRIF) analogs preferential for either the SRIF receptor 2 (SSTR2) or the SSTR5 subtype demonstrated a variable suppression of GH and PRL release from GH-secreting human adenomas. These data suggested the concept of SSTR subtype specificity in such tumors. In the present study the quantitative expression of messenger ribonucleic acid (mRNA) for the 5 SSTR subtypes and the inhibitory effects of SRIF14; SRIF28; octreotide; the SSTR2-preferential analog, BIM-23197; and the SSTR5-preferential analog, BIM-23268, on GH and PRL secretion were analyzed in cells cultured from 15 acromegalic tumors. RT-PCR analysis revealed a consistent pattern of SSTR2 and SSTR5 mRNA expression. SSTR5 mRNA was expressed at a higher level (1052 +/- 405 pg/pg glyceraldehyde-3-phosphate dehydrogenase) than SSTR2 mRNA (100 +/- 30 pg/pg glyceraldehyde-3-phosphate dehydrogenase). However, only SSTR2 mRNA expression correlated with the degree of GH inhibition induced by SRIF14, SRIF28, and BIM-23197. The SSTR5-preferential compound inhibited GH release in only 7 of 15 cases. In cells cultured from the 10 mixed adenomas that secreted both GH and PRL, RT-PCR analysis revealed a consistent coexpression of SSTR5, SSTR2, and SSTR1 mRNA. In all cases SRIF14, SRIF28, and the SSTR5-preferential analog, BIM-23268, significantly suppressed PRL secretion, with a mean maximal inhibition of 48 +/- 4%. In contrast, the SSTR2-preferential analogs, BIM-23197 and octreotide, were effective in suppressing PRL in only 6 of 10 cases. In cells cultured from adenomas taken from patients partially responsive to the SRIF analog, octreotide, partial additivity in suppressing both GH and PRL secretion was observed when the SSTR2- and SSTR5-preferring analogs, BIM-23197 and BIM-23268, were tested in combination. Our data show a highly variable ratio of the SSTR2 and SSTR5 transcripts, according to tumors. The SSTR2-preferring compound consistently inhibits GH release, whereas the SSTR5-preferring compound is the main inhibitor of PRL secretion. When both drugs are combined, the partial additivity observed in mixed GH- plus PRL-secreting adenomas may be of interest in the therapeutic approach of such tumors.
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PMID:Human somatostatin receptor subtypes in acromegaly: distinct patterns of messenger ribonucleic acid expression and hormone suppression identify different tumoral phenotypes. 1069 Aug 91


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