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)

We have examined normal T-cells and T-cell lines with respect to expression of various somatostatin receptor subtypes (SSTR1--5) using RT-PCR and PCR. To evaluate the function of these receptors we have further studied the effects of subtype specific signalling on T-cell adhesion using somatostatin analogs specific for various receptors as probes. Human T-lymphocytes showed SSTR expression related to activation and stage of differentiation. Normal T-cells (peripheral blood, T-cell clone) and T-leukaemia cell lines expressed SSTR2, SSTR3 and SSTR4. Normal T-cells expressed SSTR1 and SSTR5 while T-leukaemia lines did not. SSTR5 was selectively expressed in activated normal T-cells. T-lymphocytes produced no somatostatin themselves. Somatostatin and somatostatin analogs specific for SSTR2 and/or SSTR3 enhanced adhesion of T-cells to fibronectin (FN), and to a certain extent, also to collagen type IV (CIV) and laminin (LAM). T-lymphocytes express multiple SSTR and somatostatin may therefore regulate lymphocyte functions via distinct receptor subtypes as shown here for adhesion to extracellular matrix components (ECM) via SSTR2 and SSTR3. SSTR expression also distinguishes normal and leukaemic T-cells. Our findings suggest that SSTR subtypes may be useful targets for therapy during inflammatory diseases and malignancies affecting lymphocytes.
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PMID:Somatostatin receptor (SSTR) expression and function in normal and leukaemic T-cells. Evidence for selective effects on adhesion to extracellular matrix components via SSTR2 and/or 3. 1147 28

The effects of somatostatin (SRIF) are mediated through five distinct G-protein-coupled receptors (SSTR1-5). In the present study, pituitary cells from 6-week-old chickens were subjected to reverse hemolytic plaque assays for growth hormone (GH) in the presence of SSTR subtype specific nonpeptidyl agonists. A SSTR2 selective agonist (L-779,976) potently inhibited both basal and GH-releasing hormone (GHRH)-stimulated GH release at low nanomolar concentrations. A SSTR5 agonist (L-817,818) inhibited GH release only under basal conditions and in a subpopulation of somatotrophs. In contrast, a SSTR4 selective agonist (L-803,087) used at high nanomolar concentrations modestly stimulated GH release under basal conditions but did not influence GHRH-stimulated GH secretion. The SSTR1 and SSTR3 specific agonists did not affect GH secretion under any condition tested. Reverse transcription-polymerase chain reaction (RT-PCR) and Northern blot analysis using a partial cDNA for chicken SSTR2 showed relatively high levels of SSTR2 mRNA in the anterior pituitary (both in the caudal and cephalic lobes) and brain and detectable levels in liver, muscle, heart and small intestine. These results indicate that SSTR2 is the primary mediator of the inhibitory effects of SRIF on GH secretion in chickens.
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PMID:Identification of the somatostatin receptor subtypes involved in regulation of growth hormone secretion in chickens. 1151 55

1. The diverse physiological actions of somatostatin are mediated by a family of G-protein coupled receptors (SSTRs). Several peptide analogues of somatostatin such as octreotide have been developed for therapeutic use, including treatment of gastrointestinal disorders such as secretory diarrhoea. However, their development as anti-diarrhoeal agents has been limited by poor oral bioavailability, necessitating parenteral administration. This in vitro study investigated the anti-secretory potential of a group of novel, non-peptide, somatostatin-receptor agonists that selectively activate specific SSTR subtypes to assess their potential for oral administration. 2. The ability of the agonists to inhibit forskolin-stimulated chloride secretion was measured using a sensitive bioassay system in isolated rat colonic mucosa. 3. The SSTR-2 selective agonist, L-779,976 was 10-times more potent than octreotide as an inhibitor of secretion when added to the basolateral surface of rat colon. Non-peptide agonists selective for SSTR1 (L-797,591), SSTR3 (L-796,778), SSTR4 (L-803,087) or SSTR5 (L-817,818) showed little or no anti-secretory activity in this preparation. 4. L-779,976 was able to inhibit secretion when applied to the luminal surface at sub-micromolar concentrations suggesting that it can cross the colonic epithelium. The anti-secretory potency of luminal L-779,976 was increased 3 fold in the presence of GF120918, a known inhibitor of P-glycoprotein. 5. Non-peptide somatostatin receptor agonists may provide a basis for the development of new, orally available anti-diarrhoeal therapies.
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PMID:Anti-secretory properties of non-peptide somatostatin receptor agonists in isolated rat colon: luminal activity and possible interaction with P-glycoprotein. 1190 57

The ability of both somatostatin (SS) and its stable analogues to inhibit cell growth depends on the stimulation of specific membrane receptors (SSTR1-5), which belong to the G protein-coupled receptor family. Accumulating evidence suggests that the SSTR2 plays a major role in mediating cell cycle arrest, and it is also clear that SHP-1, a cytoplasmic phosphotyrosine phosphatase (PTP), is an essential component of the SSTR2-mediated cytostatic effect. In contrast, the possibility that SSTR2 activation may also lead to increased apoptosis is still beyond debate, despite SHP-1 activation is also able to promote cell death in several cell types. In the present work we have investigated the ability of SSTR2 to induce apoptosis in HL-60 cells. We have found that HL-60 cells uniquely express the SSTR2 subtype, and that stimulation of SSTR2 with the SS analogue SMS 201-995 results in an increased cell death. In all, these findings demonstrate that activation of SSTR2 promotes apoptosis in HL-60 cells. Moreover, in contrast with the proapoptotic mechanism previously reported for SSTR3, cell death induced by activation of SSTR2 is independent from accumulation of p53.
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PMID:Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53. 1191 46

Although peptide hormone receptors commonly exert their actions at the plasma membrane the cellular mechanisms that route the receptor proteins to the cell surface during biosynthesis are not well characterized. Here we report on the identification of a plasma membrane targeting sequence of rat somatostatin receptor subtype 3. While type 3 somatostatin receptors are present almost exclusively at the cell surface, type 1 receptors localize in addition largely in intracellular vesicular compartments. Chimeric receptors were constructed between rat somatostatin receptors 3 and 1. They were tagged by recombinant DNA techniques with a herpes simplex virus glycoprotein D epitope at the carboxyl-termini to facilitate their detection using fluorescence microscopic methods. Following transfection of the constructs in human embryonic kidney and rat insulinoma cells the chimeric receptors were analyzed by indirect immunofluorescence using anti-epitope monoclonal antibody and confocal laser scanning microscopy. The results demonstrate that the amino-terminal domain of somatostatin receptor 3 suffices to guide chimeric receptors to the cell surface. In marked contrast, chimeric receptors that lack this sequence but contain instead the amino-terminus of somatostatin type 1 receptor localize in an intracellular vesicular compartment.
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PMID:Presence of a plasma membrane targeting sequence in the amino-terminal region of the rat somatostatin receptor 3. 1193 11

Several tumors overexpress somatostatin receptors (SSTR) and can thus be imaged with radiolabeled analogues of somatostatin. Tc-99m depreotide is a new radiolabeled somatostatin analogue that shows high affinity for SSTR2, SSTR3, and SSTR5 subtypes. It has been recently FDA-approved for use in the evaluation of indeterminate solitary pulmonary nodules. SPECT with Tc-99m depreotide is highly accurate in this clinical setting and may be preferable to FDG-PET because of its lower cost and wider availability. Large studies are also underway to evaluate the accuracy of Tc-99m depreotide in staging of lung cancer.
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PMID:Somatostatin receptor imaging of non-small cell lung cancer with 99mTc depreotide. 1196 4

The effects of somatostatin (SRIF) are mediated through the seven transmembrane receptor family that signals via Gi/Go. To date, five distinct SRIF receptors have been characterized and designated SSTR1-5. We have characterized the SRIF receptor that mediates the increase in [Ca(2+)](i) and insulin secretion in HIT-T15 cells (Simian virus 40-transformed Syrian hamster islets) using high affinity, subtype selective agonists for SSTR1 (L-797,591), SSTR2 (L-779,976), SSTR3 (L-796,778), SSTR4 (L-803,087), SSTR5 (L-817,818) and PRL-2903, a specific SSTR2 antagonist. In the presence of arginine vasopressin (AVP), SRIF increased [Ca(2+)](i) and insulin secretion. Treatment with the SSTR2 agonist L-779,976 resulted in similar responses to SRIF. In addition, L-779,976 increased both [Ca(2+)](i) and insulin secretion in a dose-dependent manner. Treatment with L-779,976 alone did not alter [Ca(2+)](i) or basal insulin secretion. In the presence of AVP, all other SRIF receptor agonists failed to increase [Ca(2+)](i) and insulin secretion. The effects of SRIF and L-779,976 were abolished by the SSTR2 antagonist PRL-2903. Our results suggest that the mechanism underlying SRIF-induced insulin secretion in HIT-T15 cells be mediated through the SSTR2.
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PMID:SSTR2 mediates the somatostatin-induced increase in intracellular Ca(2+) concentration and insulin secretion in the presence of arginine vasopressin in clonal beta-cell HIT-T15. 1208 89

Five somatostatin receptors (SSTRs) bind somatostatin-14 (S-14) and somatostatin-28 (S-28), but SSTR5 has the highest affinity for S-28. To determine whether S-28 acting through SSTR5 mediates inhibition of glucagon-like peptide-1 (GLP-1), fetal rat intestinal cell cultures were treated with somatostatin analogs with relatively high specificity for SSTRs 2-5. S-28 dose-dependently inhibited GLP-1 secretion stimulated by gastrin-releasing peptide more potently than S-14 (EC(50) 0.01 vs. 5.8 nM). GLP-1 secretion was inhibited by an SSTR5 analog, BIM-23268, more potently than S-14 and nearly as effectively as S-28. The SSTR5 analog L-372,588 also suppressed GLP-1 secretion equivalent to S-28, but a structurally similar peptide, L-362,855 (Tyr to Phe at position 7), was ineffective. An SSTR2-selective analog was less effective than S-28, and an SSTR3 analog was inactive. Separate treatment with GLP-1-(7-36)-NH(2) increased S-28 and S-14 secretion by three- and fivefold; BIM-23268 abolished S-28 without altering S-14, whereas the SSTR2 analog was inactive. The results indicate that somatostatin regulation of GLP-1 secretion occurs via S-28 through activation of SSTR5. GLP-1-stimulated S-28 secretion is also autoregulated by SSTR5 activation, suggesting a feedback loop between GLP-1 and S-28 modulated by SSTR5.
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PMID:Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. 1211 May 36

The peptide somatostatin (SST) is widely synthesized in the brain and periphery and acts through a family of five receptors (SSTR1-5) to exert numerous effects. A gene product related to SST, cortistatin (CST), also interacts with SSTR1-5. Here we have investigated the regulation of SSTR1-5 and of CST in SST knockout (SSTKO) mice. The five SSTRs were quantitated individually by subtype-selective binding analysis, by immunocytochemistry, and by mRNA measurement and showed, in the brain of SSTKO mice, up-regulation of subtypes 1, 2, 4, and 5, and down-regulation of SSTR3. Peripheral tissues displayed both subtype- and tissue-specific changes in SSTR1-5 mRNA levels of expression. Lack of SST did not up-regulate normal CST expression in brain nor did it induce its expression in the periphery. SST-like immunoreactivity, however, was induced in the proximal midgut in SSTKO animals, suggesting intestinal expression of a novel SST-like gene.
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PMID:Brain somatostatin receptors are up-regulated in somatostatin-deficient mice. 1214 48

Proliferative retinopathies account for the majority of cases of vision loss throughout the world. Currently accepted therapy for retinopathy consists of retinal ablation by panretinal laser photocoagulation or cryotherapy. This technique is not without deleterious effects to patients, including diminished night vision, reduced peripheral vision and loss of precise vision, decreasing visual acuity by one to two lines in magnitude. One promising area of research into pharmacotherapeutics for retinopathies, especially proliferative diabetic retinopathy, involves the use of synthetic analogues of somatostatin. The rationale for somatostatin as a therapeutic agent for retinal neovascularization is discussed. Somatostatin analogues such as octreotide have shown promise as a safe and effective treatment for severe proliferative diabetic retinopathy by blocking the local and systemic production of growth hormone and insulin-like growth factor type 1 associated with angiogenesis and endothelial cell proliferation. There are also observations suggesting an autocrine and paracrine effect of somatostatin, perhaps directly on retinal cells, which are known to express somatostatin receptors (SSTR). SSTR2 and SSTR3 are the most important receptor subtypes mediating growth hormone secretion and endothelial cell cycle arrest, retinal endothelial cell apoptosis and release of insulin. Thus, analogues that target these receptor subtypes may prove more useful. Long-acting somatostatin analogues are currently being tested for treatment of diabetic retinopathy and are, in fact, the only therapeutic alternative for patients who fail panretinal photocoagulation. Whether such a therapy may also prove effective for other retinal vascular proliferative diseases such as retinopathy of prematurity and age-related macular degeneration remains an open question that deserves attention, given our new understanding of the cellular and molecular mechanisms by which somatostatin may exert its antiangiogenic effects.
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PMID:Somatostatin analogues as drug therapies for retinopathies. 1258 62


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