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 pharmacology, signal transduction, and coupling to G proteins of the rat somatostatin (SRIF) receptor (SSTR)1 have been characterized in transfected Chinese hamster ovary (CHO) (K1 strain) cells. The expressed receptor exhibited saturable, high affinity binding of several radioiodinated SRIF analogues. Three different radioligands were used to determine the pharmacological properties of this SSTR subtype. [125I-Tyr11]SRIF-14 (125I-S-14), [Leu8,D-Trp22,125I-Tyr25]SRIF-28 (125I-S-28), and cyclo(D-Trp-Lys-Abu-Phe-MeAla-125I-Tyr) (125I-peptide C) displayed the following rank order of affinity (Kd) for the SSTR1 subtype: 125I-S-14 > or = 125I-S-28 > 125I-peptide C. Competition of 125I-S-14 with S-14, S-28, or peptide C displayed the same rank order of potency. Chemical cross-linking of specifically bound 125I-S-28 to membranes from CHO cells expressing the receptor indicated that the molecular weight of the SSTR1 expressed in CHO cells is approximately 70,000, suggesting that it is heavily glycosylated. Previous reports have suggested that the human SSTR1 [Mol. Pharmacol. 42:28-34 (1992)] couples poorly to G proteins. The coupling of the rat SSTR1 to G proteins was demonstrated by three independent methods. (a) Binding of 125I-S-14 to the SSTR1 subtype was inhibited in a dose-dependent fashion by incubation of membranes with guanosine-5'-O-(3-thio)triphosphate. (b) Treatment of cells with pertussis toxin decreased binding by 80%. (c) Immunoprecipitation of 125I-S-14 binding was observed with antiserum specific for Gi alpha 1,2, but not with antiserum specific for Gs alpha, in membranes from transfected cells. In CHO cells transfected with the SSTR1 cDNA, SRIF inhibited forskolin-stimulated cAMP accumulation by up to 50%, in a dose-dependent fashion (ED50 = 1.1 nM). Pertussis toxin treatment decreased both the efficacy and the potency of the SRIF-mediated inhibition of cAMP accumulation (from 50% to 22%), compared with control untreated cells. These data suggest that the rat SSTR1 inhibits cAMP accumulation by coupling to pertussis toxin-sensitive G proteins.
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PMID:Rat somatostatin receptor type 1 couples to G proteins and inhibition of cyclic AMP accumulation. 814 28

Angiotensin II acts on at least two distinct receptor subtypes (AT1 and AT2). Most known effects of angiotensin II in adult tissues are attributable to the AT1 receptor. The function of AT2 receptor is undefined, but its abundant expressions in fetal tissues, immature brain, skin wound, and atretic ovarian follicles suggest a role in growth and development. Previous studies suggested that AT2 receptor may not be G protein-coupled. Here, from a rat fetus expression library, we cloned a cDNA encoding a unique 363-amino acid protein with pharmacological specificity, tissue distribution, and developmental pattern of the AT2 receptor. It is 34% identical in sequence to the AT1 receptor, sharing a seven-transmembrane domain topology. A review of prior data on other receptors suggests that this receptor may belong to a unique class of seven-transmembrane receptors (including somatostatin SSTR1, dopamine D3, and frizzled protein Fz) for which G protein coupling has not been demonstrated. All members of this class exhibit fetal and developmental and/or neuronal-specific expression. A conserved motif in the third intracellular loop, distinguishing this class from "classical" G protein-coupled receptors, may mediate novel intracellular effects.
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PMID:Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. 822 10

The tissue distribution of mRNA encoding five somatostatin receptor subtypes, SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, was determined in adult rat tissues by solution hybridization/nuclease protection analysis using sequence-specific cRNA probes. In the central nervous system, SSTR1 and SSTR2 mRNA were expressed widely, with highest levels in hippocampus, hypothalamus, cortex, and amygdala and expression of both isoforms in cerebellum and spinal cord. Expression of SSTR3 was also widespread, occurring in all brain regions examined, with the highest level of expression in the cerebellum. SSTR4 mRNA was detected in most brain regions, with highest levels occurring in the hippocampus, cortex, and olfactory bulb. No detectable levels were found in cerebellum. SSTR5 showed a unique pattern of expression in the central nervous system, being found primarily in the hypothalamus and preoptic area. In peripheral tissues, high levels of SSTR1 and SSTR2 mRNA were found in pituitary and spleen. SSTR1 mRNA was also found in the heart and intestine, SSTR2 was detected in pancreas, and both isoforms were expressed in stomach. Expression of SSTR3 was noted in heart, liver, stomach, intestine, kidney, spleen, and pituitary. The patterns of expression were similar for SSTR4 and SSTR3 mRNA; however, SSTR4 was not expressed in liver. SSTR5 was expressed predominantly in the pituitary, but detectible levels were observed in spleen and intestine. Thus, the SSTR subtype mRNA showed both a tissue-specific and overlapping pattern of expression. Taken together with SSTR-specific signal transduction systems, this probably explains the diverse physiological actions of somatostatin.
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PMID:Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. 824 78

While trying to identify new members of the somatostatin receptor family of G protein-coupled receptors, we isolated cDNAs from a mouse brain library encoding two related receptor-like proteins, designated msl-1 and msl-2, of 380 and 372 amino acids, respectively. There was 61% identity and 71% similarity between the sequences of msl-1 and msl-2. Among members of the G protein-coupled receptor superfamily, the sequences of both msl-1 and msl-1 were most closely related to those of the somatostatin receptors (SSTRs), having approximately 35% identity with the sequence of SSTR1. Transient expression in COS-1 cells showed that msl-1 and msl-2 did not bind somatostatin. Rather they bound opioids selectively and with high affinity and had the pharmacological properties of kappa and delta opioid receptors, respectively. Indeed, the sequence of msl-2 was identical to that of a delta opioid receptor recently cloned by other workers. Functional characterization of kappa/msl-1 and delta/msl-2 opioid receptors showed that they were coupled to G proteins and mediated opioid receptor class-specific agonist inhibition of forskolin-stimulated cAMP formation. RNA blotting studies and in situ hybridization histochemistry showed that kappa opioid receptor mRNA was expressed at high levels in brain in the neocortex, hippocampus, amygdala, medial habenula, hypothalamus (arcuate and paraventricular nuclei), locus ceruleus, and parabrachial nucleus, suggesting that this receptor may play a role in arousal and regulation of autonomic and neuroendocrine functions.
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PMID:Cloning and functional comparison of kappa and delta opioid receptors from mouse brain. 839 75

The mRNA distribution in the brain and the coupling to cellular effector systems of four somatostatin receptors (SSTR1-4) was studied. All four SRIF receptor subtypes were expressed in cortex and hippocampus. In addition, SSTR1 mRNA was relatively abundant in the spinal cord whereas SSTR2 mRNA was also present in the striatum. The SSTR3 gene was predominantly expressed in the olfactory bulb and in the cerebellum. Conflicting results about the effector coupling of SSTR1-3 have been published previously. We have stably expressed human SSTR1-4 in HEK 293 human embryonal kidney cells. Agonist binding to the receptor subtypes, including the recently cloned SSTR4, inhibited the formation of forskolin-induced cAMP. Is is concluded that, in an appropriate cellular environment, all four receptor subtypes can functionally couple to the inhibition of adenylyl cyclase.
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PMID:Distribution and second messenger coupling of four somatostatin receptor subtypes expressed in brain. 840 11

Somatostatin (SRIF) analogues display anti-tumor properties believed to be mediated by specific cell surface somatostatin receptors (SSTR). SSTR subtypes have unique pharmacological properties, including specific GTP-binding protein coupling, ion channel regulation, and cAMP inhibition; therefore, identification of isotypes expressed in tumor cells facilitates current efforts to design potent anti-tumor SRIF analogues. Human and rodent solid, transplantable tumors and tumor cell lines were examined for gene expression of SSTR1, SSTR2 and SSTR3 by reverse transcription of tumor mRNA and subsequent amplification of cDNA by the polymerase chain reaction, using SSTR subtype-specific oligonucleotide primers. SSTR2 mRNA transcripts were observed in all of the tumor cell lines examined. SSTR1 gene expression was seen in several human and rat tumor types, and SSTR3 gene expression observed in two rodent tumor types. SSTR mRNA-positive tumors are expected to possess membrane-bound receptors which could potentially interact with anti-tumor SRIF analogues.
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PMID:Somatostatin receptor subtype gene expression in human and rodent tumors. 851 84

Somatostatin (SST) is one of the major peptide transmitters in the mammalian central nervous system and also seems to exert specific functions during brain development. In contrast to ligand binding experiments, by which two pharmacologically different binding sites were characterized, molecular cloning techniques have led to the identification of at least five different receptor subtypes (SSTR1-5), which according to RNA blot analyses seem to be differentially distributed and regulated in the developing brain. In order to provide more precise data on the distribution of SSTR1 during ontogenesis, we have performed an in situ hybridization analysis, using a 35S-labelled RNA probe, in the developing rat cortex between embryonic day (E)12 and adulthood. Within the cortical plate, expression of SSTR1 gene was first detected in parallel with the establishment of the deep laminae V/VI at E16, thereby following the characteristic morphogenetic gradients of cortical plate construction. Thus, with the subsequent addition of cells along the radial dimension, e.g. the deposition of the supragranular neurons beyond E18, the hybridization signal spreads as an uniform homogenous band through the entire cortical plate, whereby silver grains reach their peak density around birth. Similar developmental gradients were observed along the lateromedial and frontooccipital dimension, whereby SSTR1 transcripts were detected near the frontal pole and the lateral cortical areas roughly 2 days before they appeared in the occipital and medial cortical anlage, respectively. From the initially homogenous distribution, two distinct SSTR1 mRNA-positive bands coextensive with laminae V/VI and II/III, respectively, and sparing lamina IV evolved during the first postnatal week, the grain density of which decreased during further postnatal development. Within the hippocampal formation, SSTR1 transcripts were initially observed at E18 in the subicular complex, and after birth also extending into the neighboring CA1 region. During the 1st and 2nd postnatal week, silver grains were observed over the pyramidal cell layer of CA2 and CA3 and as a faint supragranular band in the dentate gyrus. Similar to the isocortex, grain density decreased thereafter. Hypothetically, the pronounced temporospatial regulation of SSTR1 gene expression during brain development can be correlated with (1) the establishment and eventual reduction of transient cortical SSTergic neuron populations described for late pregnancy and early postnatal development and (2) a receptor subtype exchange during maturation as evidenced by the late (from postnatal day 7 onward) appearance of e.g. SSTR3.
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PMID:Distribution of somatostatin receptor subtype 1 mRNA in the developing cerebral hemispheres of the rat. 857 44

In several tissues including gastric mucosa, somatostatin displays various biological effects. Five seven-transmembrane-domain somatostatin receptor subtypes (SSTR1-5) have been recently cloned and only SSTR1 has been shown to be present in the human stomach. We used the polymerase chain reaction on reverse transcripts (RT-PCR) to characterize further the SSTR's mRNAs in human and rat gastric mucosae and in the human gastric tumoral cell-line HGTL. The SSTR1-5's mRNAs were found in both human fundic and antral mucosae as well as in the HGT1 cell and rat antrum. The four SSTR2-5's mRNA's but not SSTR1's were detected in the rat fundic mucosa. Furthermore, the use of rat isolated and purified fundic mucosal cells allowed us to localize SSTR2-5 in the parietal cell-enriched fraction, whereas SSTR2 and SSTR5 were the only subtypes found in the endocrine cell-enriched fraction. These results are the first to demonstrate the presence of five SSTR's mRNA subtypes in the stomach.
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PMID:Messenger RNA expression of somatostatin receptor subtypes in human and rat gastric mucosae. 862 62

We investigated somatostatin receptors (SSTRs) in surgical specimens of prostate cancer and benign prostate hyperplasia (BPH), a normal immortalized epithelial cell line (PNT1), epithelial cancer cell lines, and stromal cells in short-term culture derived from normal and BPH biopsies. Cross-linking studies with 125I-Tyr11-SRIF-14 (125I-SRIF) and the SRIF analog 125I-BIM-23104 identified one major 57-kDa band both in surgical specimens and in epithelial and stromal cells cultures. In membrane-enriched fractions and whole stromal cells from a normal prostate and from one BPH, a single type of SSTR was characterized (Kd = 6.10(-9) and 10(-8) M, respectively, Bmax = 1.6 pmol per mg of proteins). mRNA for SSTR1 was detected in all epithelial and stromal cells tested except for PNT1, while SSTR2 mRNA was detected in one BPH stromal cell culture. BIM-23104 had no effect on the in vitro growth of the epithelial cells tested. Conversely, 10(-10) M BIM-23104 induced >50% growth inhibition of stromal cells after 6 days in culture. These results may have implications for therapeutic strategies using SRIF analogs in BPH and prostate cancer.
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PMID:Somatostatin receptors in prostate tissues and derived cell cultures, and the in vitro growth inhibitory effect of BIM-23014 analog. 867 27

The somatostatin (SRIF) receptors (SSTRs) 1 and 2 bind SRIF and SRIF 28 with high affinity, although a number of synthetic hexapeptide and octapeptide analogs of SRIF bind selectively to SSTR2. Extracellular loop three and its adjoining trans-membrane-spanning regions contain elements essential for the binding of such analogs to murine SSTR2. In particular, a stretch of amino acids from residues 294-297 (FDFV) in murine SSTR2 in trans-membrane domain seven can determine affinity for the SSTR2-selective analogs. Within this region, Phe294 has previously been predicted to be essential for the binding of octapeptides (Kaupmann, K., Bruns, C., Raulf, F., Weber, H., Mattes, H., and Lubbert, H. (1995) EMBO J. 14, 727-735) based on the observation that SSTR1 can bind the octapeptide SMS-201-995 with reasonable affinity after a Ser-to-Phe conversion in the analogous region of this receptor (SSTR1S305F). We find that SSTR1S305F has low affinity for a number of SSTR2-selective hexapeptides, suggesting that these analogs have different binding requirements than SMS-201-995. A correlation is seen between the ability of SSTR1S305F to bind hexapeptide analogs and the presence of a phenylalanine, but not tyrosine, at position two in these small cyclic molecules. Thus, a single hydroxyl group in hexapeptides can play a critical role in determining receptor binding to these receptor mutants. We also find that the second extracellular loop of SSTR1 is important for the selectivity of certain SRIF agonists for binding to SSTR1. Taken together, our data indicate that there are multiple elements in the somatostatin receptors that can determine the binding affinity and selectivity of peptide analogs.
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PMID:Identification of ligand binding determinants in the somatostatin receptor subtypes 1 and 2. 870 67


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