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)

Somatostatin (SST), a regulatory peptide, is produced by neuroendocrine, inflammatory, and immune cells in response to ions, nutrients, neuropeptides, neurotransmitters, thyroid and steroid hormones, growth factors, and cytokines. The peptide is released in large amounts from storage pools of secretory cells, or in small amounts from activated immune and inflammatory cells, and acts as an endogenous inhibitory regulator of the secretory and proliferative responses of target cells that are widely distributed in the brain and periphery. These actions are mediated by a family of seven transmembrane (TM) domain G-protein-coupled receptors that comprise five distinct subtypes (termed SSTR1-5) that are endoded by separate genes segregated on different chromosomes. The five receptor subtypes bind the natural SST peptides, SST-14 and SST-28, with low nanomolar affinity. Short synthetic octapeptide and hexapeptide analogs bind well to only three of the subtypes, 2, 3, and 5. Selective nonpeptide agonists with nanomolar affinity have been developed for four of the subtypes (SSTR1, 2, 3, and 4) and putative peptide antagonists for SSTR2 and SSTR5 have been identified. The ligand binding domain for SST ligands is made up of residues in TMs III-VII with a potential contribution by the second extracellular loop. SSTRs are widely expressed in many tissues, frequently as multiple subtypes that coexist in the same cell. The five receptors share common signaling pathways such as the inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G-protein-dependent mechanisms. Some of the subtypes are also coupled to inward rectifying K(+) channels (SSTR2, 3, 4, 5), to voltage-dependent Ca(2+) channels (SSTR1, 2), a Na(+)/H(+) exchanger (SSTR1), AMPA/kainate glutamate channels (SSTR1, 2), phospholipase C (SSTR2, 5), and phospholipase A(2) (SSTR4). SSTRs block cell secretion by inhibiting intracellular cAMP and Ca(2+) and by a receptor-linked distal effect on exocytosis. Four of the receptors (SSTR1, 2, 4, and 5) induce cell cycle arrest via PTP-dependent modulation of MAPK, associated with induction of the retinoblastoma tumor suppressor protein and p21. In contrast, SSTR3 uniquely triggers PTP-dependent apoptosis accompanied by activation of p53 and the pro-apoptotic protein Bax. SSTR1, 2, 3, and 5 display acute desensitization of adenylyl cyclase coupling. Four of the subtypes (SSTR2, 3, 4, and 5) undergo rapid agonist-dependent endocytosis. SSTR1 fails to be internalized but is instead upregulated at the membrane in response to continued agonist exposure. Among the wide spectrum of SST effects, several biological responses have been identified that display absolute or relative subtype selectivity. These include GH secretion (SSTR2 and 5), insulin secretion (SSTR5), glucagon secretion (SSTR2), and immune responses (SSTR2).
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PMID:Somatostatin and its receptor family. 1043 61

The existence of receptor dimers has been proposed for several G protein-coupled receptors. However, the question of whether G protein-coupled receptor dimers are necessary for activating or modulating normal receptor function is unclear. We address this question with somatostatin receptors (SSTRs) of which there are five distinct subtypes. By using transfected mutant and wild type receptors, as well as endogenous receptors, we provide pharmacological, biochemical, and physical evidence, based on fluorescence resonance energy transfer analysis, that activation by ligand induces SSTR dimerization, both homo- and heterodimerization with other members of the SSTR family, and that dimerization alters the functional properties of the receptor such as ligand binding affinity and agonist-induced receptor internalization and up-regulation. Double label confocal fluorescence microscopy showed that when SSTR1 and SSTR5 subtypes were coexpressed in Chinese hamster ovary-K1 cells and treated with agonist they underwent internalization and were colocalized in cytoplasmic vesicles. SSTR5 formed heterodimers with SSTR1 but not with SSTR4 suggesting that heterodimerization is a specific process that is restricted to some but not all receptor subtype combinations. Direct protein interaction between different members of the SSTR subfamily defines a new level of molecular cross-talk between subtypes of the SSTR and possibly related receptor families.
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PMID:Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers. 1071 1

A new line (FP) of human foetal lung fibroblasts was analysed for the expression of functional, G-protein coupled somatostatin receptors (SSTR). By means of RT-PCR, we identified the expression of SSTR1, SSTR2, SSTR3 and SSTR4, but not SSTR5, subtypes. The same technical approach evidenced the expression of stimulatory (alphas) and inhibitory (alphai1, alphai2 and alphai3) G-protein subunits. The functionality of SSTR was established from the observation of a dose-dependent inhibitory role of SST upon isoproterenol-stimulated adenylyl cyclase activity, an effect that involves G-protein action. Moreover, the functionality of G-proteins was assessed by means of experiments with forskolin and a nonhydrolysable GTP analogue that showed either Gi or Gs activation in the regulation of adenylyl cyclase. Present results represent a first pharmacological characterization of this new line of human foetal lung fibroblasts. The selective presence of some SSTR subtypes and G-protein subunits in addition to the regulatory network of the adenylyl cyclase pathway are features of recognized involvement in cell growth mechanisms. It is of interest for a cell class widely used to study this topic but also important in lung physiology and pathophysiology.
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PMID:Identification of functional somatostatin receptors and G-proteins in a new line of human foetal lung fibroblasts. 1101 9

Malignant melanoma is a neuroendocrine tumor that contains somatostatin receptors (SSTRs). Adjuvant therapy for melanoma is limited. Because melanomas arise from neural crest cells, we sought to evaluate the distribution of SSTR subtypes found in these tumors and their functional significance by imaging with 111In-pentetreotide scintigraphy (OctreoScan). Octreotide binds with greatest affinity to SSTR2 and SSTR5. Studying the expression of SSTRs in melanoma may demonstrate a potential role for octreotide in the treatment of melanoma. A series of 23 melanomas from 17 patients who underwent resection of regional or distant metastases were evaluated for the presence of SSTRs by the reverse transcriptase-polymerase chain reaction (RT-PCR) using primers specific for SSTR1 through SSTR5. Identity of RT-PCR products was confirmed by Southern blot analysis. Sixteen patients underwent preoperative OctreoScan. SSTR1 was expressed in 96% of tumors, SSTR2 in 83%, SSTR3 in 61%, SSTR4 in 57%, and SSTR5 in 9%. OctreoScan imaged 63% of tumors. There was no correlation between SSTR subtype expression and OctreoScan result. Most of the melanomas expressed mRNA for SSTR1 and SSTR2, with approximately half expressing SSTR3 and SSTR4. The SSTR mRNA for SSTR2 appears to be transcribed into functional protein that binds 111In-pentetreotide in more than half of these patients. Although OctreoScan has limited sensitivity for localizing melanomas, tumors that can be imaged by OctreoScan may be amenable to adjuvant therapy with octreotide or targeted therapy with high-energy radioisotope-labeled octreotide. These studies clearly define melanoma as a neuroendocrine tumor, which may open new avenues for tumor control.
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PMID:Distribution and functional significance of somatostatin receptors in malignant melanoma. 1134 89

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 high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress the one or the other of five distinct hSSTR sub-type receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higher" high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including 99mTc-HYNIC-octreotide or 99mTc-depreotide (NEOSPECT; NEOTECT). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study "MAURITIUS" (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase IIa study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in >60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm "proof-of-principle" for their use in diagnosis as well as therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy.
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PMID:New trends in peptide receptor radioligands. 1147 64

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 high-level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled peptide analogues as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress one or the other of 5 distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress human(h) SSTR2, intestinal adenocarcinomas frequently express hSSTR3 or hSSTR4, or both of these hSSTRs. In contrast to (111)In-diethylenetriamine pentaacetic acid (DTPA)-(D)he(1)-octreotide (OctreoScan; Mallinckrodt, Petten, NL), which binds to hSSTR2 and 5 with high affinity (K(d)0.1-5 nmol/L), to hSSTR3 with moderate affinity (K(d)10-100 nmol/L), and does not bind to hSSTR1 and hSSTR4, (111)In /(90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d)200 nmol/L). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. When directly compared with (111)In-DTPA-(D)he(1)-octreotide and (111)In-DOTA-(D)he(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic imaging pattern are seen in about one third of tumor patients concerning both the tumor uptake as well as the detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a higher high-affinity binding affinity of (111)In-DOTA-(D)he(1)-Tyr(3)-octreotide for hSSTR2 (K(d)0.1-1 nmol/L). Beneficial results of receptor-mediated experimental radionuclide therapy were first reported for high-dose treatment with (111)In-DTPA-(D)he(1)-octreotide, based on the emission of Auger electrons. Phase IIa of the Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a European Study (MAURITIUS), shows in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy/GBq (90)Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the MAURITIUS study, cumulative treatment doses up to 232 mCi (90)Y-DOTA-lanreotide were given as short-term intravenous infusion. Preliminary treatment results in 154 patients indicate stable tumor disease in 41% (63 of 154) of patients and regressive tumor disease in 14% (22 of 154) of tumor patients with different tumor entities expressing hSSTR. No severe acute or chronic hematologic toxicity, change in renal or liver function parameters caused by (90)Y-DOTA-lanreotide treatment were reported for patients in the MAURITIUS trial. In two thirds of patients with neuroendocrine tumor lesions, (90)Y-DOTA-(D)he(1)-Tyr(3)-octreotide showed a higher tumor uptake and should therefore be considered the first choice for experimental receptor-based therapy. Potential indications for (90)Y-DOTA-lanreotide treatment are radioiodine-negative thyroid cancer, hepatocellular cancer, lung cancer, some brain tumors, and possibly melanomas. In conclusion, preclinical data and clinical studies confirm the potential usefulness of radiolabeled lanreotide for tumor diagnosis and therapy. However, careful consideration of the type of radiotracer used for receptor-mediated therapy should be made for the individual patient. Whole-body dosimetry should always be performed to predict doses for tumors and the critical organs, which are kidney and bone marrow.
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PMID:In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial. 1196 10

Somatostatin receptors (SSTRs) have been extensively mapped in human tumors by means of autoradiography, reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). We analyzed the SSTR type 1-5 expression by means of RT-PCR and/or IHC in a series of 81 functioning and non-functioning gastroenteropancreatic (GEP) endocrine tumors and related normal tissues. Moreover, we compared the results with clinical, pathological and hormonal features. Forty-six cases (13 intestinal and 33 pancreatic) were studied for SSTR 1-5 expression using RT-PCR, IHC with antibodies to SSTR types 2, 3, 5 and ISH for SSTR2 mRNA. The vast majority of tumors expressed SSTR types 1, 2, 3 and 5, while SSTR4 was detected in a small minority. Due to the good correlation between RT-PCR and IHC data on SSTR types 2, 3, and 5, thirty-five additional GEP endocrine tumors were studied with IHC alone. Pancreatic insulinomas had an heterogeneous SSTR expression, while 100% of somatostatinomas expressed SSTR5 and 100% gastrinomas and glucagonomas expressed SSTR2. Pre-operative biopsy material showed an overlapping immunoreactivity with that of surgical specimens, suggesting that the SSTR status can be detected in the diagnostic work-up. It is concluded that SSTRs 1-5 are heterogeneously expressed in GEP endocrine tumors and that IHC is a reliable tool to detect SSTR types 2, 3 and 5 in surgical and biopsy specimens.
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PMID:Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis. 1202 20


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