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 diverse biological effects of somatostatin (SST) are mediated through a family of G protein coupled receptors of which 5 members have been recently identified by molecular cloning. This review focuses on the molecular biology, pharmacology, expression, and function of these receptors with particular emphasis on the human (h) homologs. hSSTRs are encoded by a family of 5 genes which map to separate chromosomes and which, with one exception, are intronless. SSTR2 gives rise to spliced variants, SSTR2A and 2B. hSSTR1-4 display weak selectivity for SST-14 binding whereas hSSTR5 is SST-28 selective. Based on structural similarity and reactivity for octapeptide and hexapeptide SST analogs, hSSTR2,3, and 5 belong to a similar SSTR subclass. hSSTR1 and 4 react poorly with these analogs and belong to a separate subclass. All 5 hSSTRs are functionally coupled to inhibition of adenylyl cyclase via pertussis toxin sensitive GTP binding proteins. Some of the subtypes are also coupled to tyrosine phosphatase (SSTR1,2), Ca2+ channels (SSTR2), Na+/H+ exchanger (SSTR1), PLA-2 (SSTR4), and MAP kinase (SSTR4). mRNA for SSTR1-5 is widely expressed in brain and peripheral organs and displays an overlapping but characteristic pattern that is subtype-selective, and tissue- and species-specific. Pituitary and islet tumors express several SSTR genes suggesting that multiple SSTR subtypes are coexpressed in the same cell. Structure-function studies indicate that the core residues in SST-14 ligand Phe6-Phe11 dock within a ligand binding pocket located in TMDs 3-7 which is lined by hydrophobic and charged amino acid residues.
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PMID:The somatostatin receptor family. 767 17

Somatostatin has a modulatory role in regulating the membrane conductance in hippocampal neurons. To examine the signal transducing molecules involved in this process, we isolated the cDNA encoding the dominant rat hippocampal somatostatin receptor, SSTR4. Distribution of SSTR4 in the adult central nervous system was restricted to the hippocampus, cerebral cortex, striatum, hypothalamus, and thalamus, as determined by Northern blot analysis and in situ hybridization. In SSTR4-expressing Chinese hamster ovary cells, SSTR4 was functionally coupled not only to inhibition of adenylate cyclase, but also to activation of both arachidonate release and mitogen-activated protein (MAP) kinase cascade, with similar ED50 values. All of these pathways, including both MAP kinase kinase and MAP kinase activation, were completely blocked by pretreatment with pertussis toxin. On the other hand, neither inositol 1,4,5-trisphosphate synthesis nor intracellular Ca2+ mobilization was induced upon SSTR4 stimulation. These data indicate that the hippocampal functions of somatostatin might be mediated through diverse but selective second messenger systems activated via SSTR4 and reveal an unsuspected coupling of a neuronal SSTR subtype to a mitogenic signaling pathway. SSTR4, in addition, provides a useful system to study the Ca(2+)-independent, Gi-dependent (pertussis toxin-sensitive) pathway of MAP kinase activation.
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PMID:Functional coupling of SSTR4, a major hippocampal somatostatin receptor, to adenylate cyclase inhibition, arachidonate release and activation of the mitogen-activated protein kinase cascade. 817 84

Somatostatin possesses antisecretory and antiproliferative activity on some human tumors. We herein report that, in a human neuroblastoma cell line, the somatostatin analogue BIM 23014 inhibited mitogen-activated protein (MAP) kinase activity stimulated by either insulin-like growth factor-1, whose receptor bears a tyrosine kinase, or carbachol, which acts at a G-protein coupled receptor. In a human small cell lung carcinoma line BIM inhibited serum-stimulated MAP kinase activation. These inhibitory actions occur in a dose range quite similar to that observed for suppression of proliferation induced by the analogue in the same cell lines. The decrease in cAMP elicited by the analogue in the two cell lines is not responsible for its inhibitory action on MAP kinase and cell growth. Moreover, the analogue did not modify intracellular [Ca2+] and pH. An involvement of a phosphatase activity is suggested.
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PMID:A somatostatin analogue inhibits MAP kinase activation and cell proliferation in human neuroblastoma and in human small cell lung carcinoma cell lines. 895 39

Somatostatin significantly suppressed cell growth of the mouse insulinoma-derived cell line MIN6. MIN6 cells exhibited high-affinity binding of somatostatin with 50% inhibitory concentration value of 0.9 nM. RNA blot analysis revealed that MIN6 cells expressed only SSTR3 among the five somatostatin receptors so far identified. Treatment of MIN6 cells with somatostatin significantly reduced the serum-induced c-fos expression levels. On the other hand, somatostatin (100 nM) treatment of MIN6 cells cultured in medium containing 10% serum transiently increased c-fos expression levels to 282 +/- 4.7% and then significantly decreased them to 27 +/- 7.6% of the levels before treatment. Mitogen-activated protein (MAP) kinase activity transiently increased to 656 +/- 91.2% and decreased thereafter to 39 +/- 13.3% of the activity before the addition of somatostatin (100 nM) into the medium. In addition, the stimulatory effect of somatostatin on c-fos expression and MAP kinase activity (early effect) was not altered by pertussis toxin (PTX), whereas the suppressive effect of somatostatin on c-fos expression and MAP kinase activity (late effect) was mitigated by PTX. These findings suggest that an inhibition of c-fos expression mediated by cross talk between PTX-sensitive G protein signaling and receptor tyrosine kinase signaling is one of the mechanisms by which somatostatin inhibits cell growth in MIN6 cells.
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PMID:Involvement of MAP kinase and c-fos signaling in the inhibition of cell growth by somatostatin. 917 74

We investigated cell proliferation modulated by cholecystokinin (CCK) and somatostatin analogue RC-160 in CHO cells bearing endogenous CCKA receptors and stably transfected by human subtype sst5 somatostatin receptor. CCK stimulated cell proliferation of CHO cells. This effect was suppressed by inhibitor of the soluble guanylate cyclase, LY 83583, the inhibitor of the cGMP dependent kinases, KT 5823, and the inhibitor of mitogen-activated protein (MAP) kinase kinase, PD 98059. CCK treatment induced an increase of intracellular cGMP concentrations, but concomitant addition of LY 83583 virtually suppressed this increase. CCK also activated both phosphorylation and activity of p42-MAP kinase; these effects were inhibited by KT 5823. All the effects of CCK depended on a pertussis toxin-dependent G protein. Somatostatin analogue RC-160 inhibited CCK-induced stimulation of cell proliferation but it did not potentiate the suppressive effect of the inhibitors LY 83583 and KT 5823. RC-160 inhibited both CCK-induced intracellular cGMP formation as well as activation of p42-MAP kinase phosphorylation and activity. This inhibitory effect was observed at doses of RC-160 similar to those necessary to occupy the sst5 recombinant receptor and to inhibit CCK-induced cell proliferation. We conclude that, in CHO cells, the proliferation and the MAP kinase signaling cascade depend on a cGMP-dependent pathway. These effects are positively regulated by CCK and negatively influenced by RC-160, interacting through CCKA and sst5 receptors, respectively. These studies provide a characterization of the antiproliferative signal mediated by sst5 receptor.
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PMID:Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. 925 84

1. The operational characteristics of somatostatin (SRIF) sst4 receptors are poorly understood. In this study, we have characterized human recombinant sst4 receptors expressed in CHO cells (CHOsst4) by radioligand binding and microphysiometry. 2. Increasing concentrations SRIF or other SRIF receptor ligands inhibited specific [125I]-Tyr11-SRIF binding in CHOsst4 cell membranes with respective pIC50 values of SRIF (8.82), L-362855 (7.40), BIM-23027 (<5.5) and MK-678 (<5.5). 3. These ligands displayed agonist activity, producing concentration-dependent increases in rates of extracellular acidification (EAR) with pEC50 values of SRIF (9.6) and L-362855 (8.0), respectively. BIM-23027 and MK-678 were at least 1000 times weaker than SRIF. The SRIF maximum was about 40% of that observed with L-362855. 4. In the presence of SRIF (0.1-1 nM), concentration-effect curves to L-362855 were displaced to the right with a progressive reduction in the L-362855 maximum. 5. When cells were only exposed to a single maximally effective concentration of SRIF or L-362855, there was no difference in the magnitude of the agonist-induced increase in EAR. However, a second agonist challenge, 30 min later showed that responses to SRIF but not L-362855 were markedly desensitized. 6. When concentration-effect curves to SRIF and L-362855 were obtained by combining data from cells exposed to only a single agonist concentration, SRIF (pEC50 9.2) was approximately 20 times more potent than L-362855 (pEC50 8.0) but the maxima were the same. Responses to both SRIF and L-362855 were abolished by pertussis toxin. 7. SRIF and L-362855-induced increases in EAR were inhibited by N-ethyl isopropyl amiloride (10 microM) but were not modified by inhibitors of PKC (Go-6976), MAP kinase (PD-98059), tyrosine kinase (genistein) or tyrosine phosphatase (sodium orthovanadate). 8. The results suggest that SRIF-induced increases in EAR in CHOsst4 cells involved activation of the Na+/H+ antiporter and were mediated via Gi/Go G proteins. Responses to SRIF, but not L-362855, were subject to marked desensitization which may be a consequence of differential activation of receptor-effector coupling pathways.
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PMID:Differential agonist activity of somatostatin and L-362855 at human recombinant sst4 receptors. 983 22

It has been proposed that neurotransmitters and neuromodulators may function as neurotrophic factors during the development of the nervous system. Somatostatin (SS) was known to increase neurite outgrowth in PC12 cells, rat pheochromocytoma cell line, and cerebellar granule cells as well as Helisoma neuron. To further investigate a neurotrophic role of SS, voltage-dependent K+ and Ca2+ channel expression was studied using whole-cell patch-clamp in PC12 cells and the effect of SS was compared to that of nerve growth factor (NGF). Cyclic AMP (cAMP) level and mitogen-activated protein (MAP) kinase phosphorylation were also studied following the treatment with SS and/or NGF. Whereas NGF (50 ng/ml) increased continually the current density of the voltage-dependent K+ channel throughout 8 days treatment, SS (1 microM) increased the K+ current density on day 2 to the peak. K+ current density was decreased thereafter and was not different on day 6 from that of undifferentiated cells. Although SS did not increase voltage-dependent Ca2+ current density, it potentiated NGF-induced increase of voltage-dependent Ca2+ channel current density as well as the K+ current density. cAMP level was decreased by NGF and/or SS treatment. An increased phosphorylation of MAP kinase induced by NGF was not changed by SS treatment. These results support functionally that SS may function as a neurotrophic factor in developing nervous system.
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PMID:Somatostatin potentiates voltage-dependent K+ and Ca2+ channel expression induced by nerve growth factor in PC12 cells. 987 77

Hormones and growth factors regulate cell growth via the mitogen-activated protein (MAP) kinase cascade. Here we examine the actions of the hormone somatostatin on the MAP kinase cascade through one of its two major receptor subtypes, the somatostatin receptor 1 (SSTR1) stably expressed in CHO-K1 cells. Somatostatin antagonizes the proliferative effects of fibroblast growth factor in CHO-SSTR1 cells via the SSTR1 receptor. However, in these cells, somatostatin robustly activates MAP kinase (also called extracellular signal regulated kinase; ERK) and augments fibroblast growth factor-stimulated ERK activity. We show that the activation of ERK via SSTR1 is pertussis toxin sensitive and requires the small G protein Ras, phosphatidylinositol 3-kinase, the serine/threonine kinase Raf-1, and the protein tyrosine phosphatase SHP-2. The activation of ERK by SSTR1 increased the expression of the cyclin-dependent protein kinase inhibitor p21(cip1/WAF1). Previous studies have suggested that somatostatin-stimulated protein tyrosine phosphatase activity mediates the growth effects of somatostatin. Our data suggest that SHP-2 stimulation by SSTR1 may mediate some of these effects through the activation of the MAP kinase cascade and the expression of p21(cip1/WAF1).
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PMID:Somatostatin activation of mitogen-activated protein kinase via somatostatin receptor 1 (SSTR1). 989 10

Somatostatin (SS-14) and its structural analogue SMS 201-995 (SMS) are recognized as physiological inhibitors of multiple organs and tissue functions through specific membrane receptors (sst1-sst5). The effects of SS-14 and SMS in the growth control of the pancreatic cancer cell lines MIA PaCa-2 and PANC-1 were investigated to identify and clarify the intracellular events involved. In PANC-1 cells, SS-14 and SMS caused inhibition of their basal growth, and that stimulated by epidermal growth factor, with a maximal effect at 0.1-1 microM. To understand the inhibitory mechanisms, we investigated the effects of SS-14 and SMS on phosphotyrosine phosphatase (PTPase) activity and, more specifically, that of tyrosine phosphatase SHP-1 (PTP1C). SS-14 and SMS caused significant increases in total cellular PTPase activity, and particularly SHP-1, with maximal activation within 1 min. Inhibition of membrane tyrosine kinase and p42 MAP kinase activities was also observed, in response to SS-14 and SMS. In MIA PaCa-2 cells, SS-14 and SMS were associated with a positive growth response at 1-10 nM, after 4 days of culture in serum-free medium. Total cellular PTPase activity was slightly increased, but SHP-1 activity could not be detected; its absence in this cell line was confirmed by Western blot. Membrane tyrosine kinase activities were significantly increased by SS-14 and SMS at concentrations needed for maximal growth. p44/p42, which are constitutively active in this cell line, and p38 activities were not affected by somatostatin. In conclusion, somatostatin can exert different effects on human pancreatic cancer cell growth, depending upon the presence or absence of SHP-1. This enzyme can play a key role in the control of cell proliferation, and its cellular presence may determine the therapeutic potential of somatostatin in the control of cancer cell growth.
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PMID:Inhibitory and stimulatory effects of somatostatin on two human pancreatic cancer cell lines: a primary role for tyrosine phosphatase SHP-1. 992 4

We have previously demonstrated in CHO-K1 cells expressing recombinant human sst(4) receptors that somatostatin-induced increases in extracellular acidification are susceptible to a marked desensitisation after pretreatment with somatostatin, but not the somatostatin analogue, L-362855. In the present study, we have examined the human sst(4) receptor-mediated stimulation of p44/p42 mitogen-activated protein (MAP) kinase to determine whether this response is susceptible to a similar agonist-specific desensitisation. Western analysis using phosphospecific antibodies revealed that both somatostatin and L-362855 induced a transient stimulation of MAP kinase which could be desensitised by pretreatment with somatostatin, but not L-362855. The selective phosphoinositide (PI) 3-kinase inhibitor, LY 249002, blocked both the somatostatin-induced increase in MAP kinase phosphorylation and extracellular acidification. However, the MEK1 inhibitor, PD 98059, blocked only the sst(4) receptor-mediated stimulation of MAP kinase and not the extracellular acidification response. In summary, the human sst(4) receptor is selectively desensitised by somatostatin and not by L-362855 and signals through two different PI 3-kinase linked pathways.
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PMID:The pivotal role of phosphoinositide-3 kinase in the human somatostatin sst(4) receptor-mediated stimulation of p44/p42 mitogen-activated protein kinase and extracellular acidification. 1048 83


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