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)

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

In the present study we found that exocrine pancreatic hyperplasia observed after proximal small bowel resection is accompanied by an increase in pancreatic somatostatin (SS) content at 1 mo and an increase in the number of SS receptors at 2 wk and 1 mo after intestinal surgery. At 6 mo after small bowel resection SS content and SS receptors had returned to control values. However, the original increase in SS receptor number was accompanied by a decrease in the ability of SS to inhibit forskolin-stimulated adenylyl cyclase (AC) activity. In addition, the ability of 5'-guanylylimidodiphosphate (a nonhydrolyzable GTP analogue) to inhibit SS receptor binding was decreased in pancreatic acinar membranes from enterectomized rats at 2 wk and 1 mo after jejunoileal resection. These data suggest that there is an abnormality in the integrity of SS receptor binding site-G protein interactions and would explain the decreased inactivation of AC by SS at 2 wk and 1 mo after proximal small bowel resection.
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PMID:Somatostatin receptor-effector system in rat pancreatic acinar membranes after subtotal enterectomy. 786 12

The diverse biological actions of somatostatin (SRIF) are mediated by a family of receptors, of which five have been cloned and characterized. One of the SRIF receptor subtypes, SSTR2, has been shown to exist in two forms. SSTR2A and SSTR2B are 369 and 346 amino acids in size, respectively, and differ in length and amino acid sequence in their intracellularly located carboxyl termini. SSTR2A and SSTR2B are generated by alternative splicing of SSTR2 mRNA. We previously characterized mouse SSTR2A and showed that it could be distinguished from other cloned SRIF receptor subtypes by its high affinity for MK-678 and its lack of coupling to adenylyl cyclase. To determine whether the properties of mouse SSTR2A and SSTR2B differ, we have expressed both in COS-7 cells and characterized their ligand-binding properties and ability to couple to adenylyl cyclase. The two receptors exhibited similar affinities for a number of SSTR2-selective agonists such as MK-678. Pretreatment with SRIF of COS-7 cells expressing each receptor reduced high affinity agonist binding to both SSTR2A and SSTR2B, indicating that both receptors can be regulated. Furthermore, agonist binding to both receptors was reduced by GTP analogs and Na+, indicating that they both associate with G proteins. As shown previously, SSTR2A could not mediate SRIF inhibition of forskolin-stimulated cAMP formation. In contrast, SSTR2B was coupled to adenylyl cyclase and was able to mediate SRIF inhibition of forskolin-stimulated cAMP formation. Thus, SSTR2A and SSTR2B differ in their ability to couple to adenylyl cyclase. Because SSTR2A and SSTR2B differ only in the length and amino acid sequence of their carboxyl termini, these findings imply that the carboxyl-terminal 15 residues of SSTR2B may be involved in coupling this receptor to adenylyl cyclase.
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PMID:Splice variant of the somatostatin receptor 2 subtype, somatostatin receptor 2B, couples to adenylyl cyclase. 1021 90

Recent reports have suggested that only some of the cloned somatostatin receptors (SSTRs) are coupled to adenylyl cyclase. These studies have used both stable and transiently transfected cells or cells lacking appropriate Gi alpha and are controversial. To investigate SSTR signalling mechanisms, we have established stably transfected CHO-K1 cells expressing human genes for SSTR1-5. The effect of 0.1-100 nM SST-14 and SST-28 on forskolin (1 microM) stimulated cAMP accumulation was determined and compared to their receptor binding affinities. The 5 expressed hSSTRs bound SST-14 and SST-28 with high affinity (IC50 1.1-2.1 nM for SST-14; IC50 0.25-5.4 nM for SST-28). hSSTR1-4 bound SST-14 > SST-28 whereas hSSTR5 bound SST-28 > SST-14. Radioligand binding to hSSTR1-5 was significantly inhibited by GTP, GTP gamma S and pertussis toxin. Both SST-14 and SST-28 inhibited forskolin-induced cAMP stimulation with ED50 values which paralleled their binding affinities for the individual hSSTR subtypes. These results demonstrate that all 5 human SSTRs are functionally coupled to inhibition of adenylyl cyclase in CHO-K1 cells via pertussis toxin sensitive G proteins.
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PMID:All five cloned human somatostatin receptors (hSSTR1-5) are functionally coupled to adenylyl cyclase. 790 65

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

Somatostatin exerts multiple effects throughout the body by binding to specific somatostatin receptors. Two classes of somatostatin receptors, SRIF1 and SRIF2, have been distinguished biochemically and pharmacologically. Two cDNAs have been recently isolated that encode somatostatin receptors 1 and 2 (SSTR1 and SSTR2, respectively). The pharmacological characteristics of receptors expressing these cDNAs resemble those of the SRIF2 and SRIF1 classes of somatostatin receptors, respectively. We stably expressed the rat homologs of both receptors in Chinese hamster ovary (CHO) cells (type K1). These transfected cell lines recognized the endogenous ligands SS14 and SS28 with high affinity, whereas the synthetic analog MK678 identified only SSTR2. In preparations of CHO-SSTR1 or CHO-SSTR2 cells, SS14 and SS28 inhibited forskolin-stimulated adenylyl cyclase activity by approximately 35%, with ED50 values in the nanomolar range. The adenylyl cyclase inhibition was dependent upon the guanine nucleotide GTP and could be ablated with pertussis toxin preincubation. The present data indicate that SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase via pertussis toxin- sensitive G-proteins.
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PMID:The somatostatin receptors SSTR1 and SSTR2 are coupled to inhibition of adenylyl cyclase in Chinese hamster ovary cells via pertussis toxin-sensitive pathways. 790 16

Using a combination of polymerase chain reaction and genomic library screening we have cloned a human gene for a subtype of the somatostatin (SST) receptor (SSTR) termed human SSTR5 (hSSTR5), which is located on chromosome 16. The predicted amino acid sequence of hSSTR5 displays 75% sequence identity with a recently identified rat SSTR [Mol. Pharmacol. 42:939-946 (1992)], suggesting that it is the human homologue of this receptor. hSSTR5 consists of a 363-residue polypeptide exhibiting a putative seven-transmembrane domain topology typical of G protein-coupled receptors. The receptor displays considerable sequence identity to hSSTR1 (42%), hSSTR2 (48%), hSSTR3 (47%), and hSSTR4 (46%). Membranes prepared from COS-7 cells transiently expressing the hSSTR5 gene bound 125I-Leu8,D-Trp22,Tyr25-SST-28 (125I-LTT-SST-28) with high affinity and in a saturable manner. SST-14, SST-28, and various synthetic SST peptide agonists produced dose-dependent inhibition of radioligand binding with the following rank order of potency: LTT-SST-28 > SST-28 > D-Trp8-SST-14 > SST-14 approximately RC-160 approximately BIM 23014 > MK-678 > SMS 201-995. hSSTR5 bound SST-28 with a 12.6-fold greater affinity (Ki = 0.19 nM), compared with SST-14 (Ki = 2.24 nM), indicating that the receptor is SST-28 selective. Addition of GTP, guanosine-5'-O-(3-thio)triphosphate, Na+ ions, or pertusis toxin greatly reduced 125I-LTT-SST-28 binding, thereby indicating that hSSTR5 is coupled to pertussis toxin-sensitive G proteins. Both SST-14 and SST-28 displayed dose-dependent inhibition of forskolin-stimulated cAMP accumulation, consistent with functional coupling of the receptor to adenylyl cyclase inhibition. Northern blot analysis of SSTR5 mRNA revealed a 2.4-kilobase transcript in normal rat pituitary and GH3 rat pituitary tumor cells and a 4.0-kilobase transcript in normal human pituitary. Reverse transcriptase polymerase chain reaction revealed expression of the hSSTR gene in fetal human pituitary and hypothalamus but not in human cerebral cortex. In situ hybridization of the rat pituitary showed that SSTR5 mRNA is selectively localized in the anterior lobe. SSTR5 mRNA was not expressed in four human pituitary tumors (somatotroph adenoma, prolactinoma, and chromophobe adenomas) or in a human insulinoma. Although hSSTR5 displays approximately 75% sequence identity with rat SSTR5, the two receptors display significantly different pharmacological profiles, especially with respect to their binding affinities for the SST analogue SMS 201-995.
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PMID:Molecular cloning, functional characterization, and chromosomal localization of a human somatostatin receptor (somatostatin receptor type 5) with preferential affinity for somatostatin-28. 790 5

To elucidate the effect of somatostatin and its mechanism of action on airway beta-adrenergic function, we studied canine bronchial smooth muscle under isometric conditions in vitro. Somatostatin (10(-6) M) inhibited the salbutamol-induced relaxation, so that the salbutamol concentration-response curves were displaced to higher concentrations (P < 0.01). This inhibition was dose dependent, the concentration of somatostatin required to produce a half-maximal effect being 10(-8) M. The relaxant responses to forskolin were likewise inhibited by somatostatin, but those to dibutyryl 3',5'--adenosine cyclic monophosphate (DB-cAMP), verapamil and nitroprusside were not. Somatostatin inhibited the salbutamol-induced accumulation of intracellular cAMP. These effects were abolished by the somatostatin antagonist cyclo [7-aminoheptanoyl-Phe-D-Trp-Lys-Thr (Bz)] or pertussis toxin. These observations suggest that somatostatin down-regulates beta-adrenergic function of airway smooth muscle through activation of an inhibitory guanine nucleotide (GTP)-binding regulatory protein, Gi, coupled to adenylate cyclase.
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PMID:Pertussis toxin-sensitive airway beta-adrenergic dysfunction by somatostatin. 790 48

COS-7 cells were transfected with human somatostatin (SRIF) receptor type 1 and 2 (human SSTR1 and SSTR2, respectively) cDNAs. In human SSTR2-expressing cells, SRIF not only inhibited forskolin-induced cAMP accumulation but also stimulated phospholipase C and Ca2+ mobilization. While the inhibition of cAMP accumulation was completely reversed by pertussis toxin (PTX) treatment of the cells, SRIF-induced activation of phospholipase C and Ca2+ mobilization was partially but not completely inhibited by the toxin treatment. In human SSTR1-expressing cells, however, SRIF induced only slight inhibition of cAMP accumulation and stimulation of phospholipase C-Ca2+ system. We conclude that the transfected SSTR2 can couple to phospholipase C as well as adenylate cyclase in a stimulatory and inhibitory manner, respectively. Both PTX-sensitive and -insensitive GTP-binding proteins may be involved in the SSTR2 signal transduction mechanisms.
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PMID:Transfected human somatostatin receptor type 2, SSTR2, not only inhibits adenylate cyclase but also stimulates phospholipase C and Ca2+ mobilization. 791 18

Neurotransmitter release is frequently regulated by peptides that modulate neuronal calcium channels. Whole-cell recordings show that the ion permeability and voltage dependence of these channels are controlled by a membrane-associated pathway involving GTP-binding proteins. Here we use perforated-patch recordings to show that, in addition to this pathway, the peptide somatostatin inhibits the calcium current in chick ciliary ganglion neurons by a second soluble pathway involving a cyclic GMP-dependent protein kinase (cGMP-PK). This somatostatin inhibition of Ca2+ current did not desensitize and was not characterized by the slowing of Ca(2+)-current activation (kinetic slowing) observed in whole-cell recordings. When cGMP-PK was inhibited, somatostatin inhibition of Ca2+ current resembled that observed with whole-cell recordings. cGMP agonists mimic the effect of somatostatin only in perforated patch recordings. An endogenous cGMP-PK therefore forms part of the mechanism by which somatostatin induces a sustained inhibition of neuronal calcium channels.
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PMID:Somatostatin-induced inhibition of neuronal Ca2+ current modulated by cGMP-dependent protein kinase. 791 Mar 77


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