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)

Benign as well as malignant human prostatic tissues were evaluated for their content of somatostatin (SRIH) receptors (SRIH-R). In vitro receptor autoradiography techniques on cryostat sections were performed using 125I-labeled [Tyr3]octreotide as well as 125I-labeled [Leu8,D-Trp22,Tyr25]SRIH-28 as radioligands. SRIH-R were identified in all normal and hyperplastic prostates in the smooth muscles of the stroma, whereas the glands did not express the receptors. Muscular nodules were strongly receptor positive as well. The receptors were of high affinity (Kd = 0.4 nmol/L) and high specificity for biologically active SRIH analogs; high affinity for SRIH-14, SRIH-28, and octreotide was detected, suggesting the presence of the SSTR2 receptor subtype. In situ hybridization studies confirmed the presence of SSTR2 messenger ribonucleic acid in these tissues. Primary prostate cancers did not have SRIH-R identified with 125I-labeled [Tyr3]octreotide. However, they were expressing SRIH-R identified with 125I-labeled [Leu8,D-Trp22,Tyr25]SRIH-28, with a high affinity for SRIH-14 and SRIH-28, but low affinity for octreotide. The receptors were located on tumoral cells. In situ hybridization studies revealed a preferential expression of SSTR1. Primary human prostate cancers, therefore, express a different SRIH-R subtype than benign prostate tissue. Several veins and the ganglion cells from the prostatic plexus in the surroundings of the tumors were expressing SRIH-R with high affinity for octreotide as well. These data suggest that the human prostate as well as prostate cancers may be targets for SRIH therapy; however, SRIH analogs with different selectivities for SRIH-R subtypes are required in each case.
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PMID:Somatostatin receptors in human prostate and prostate cancer. 767 28

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

The neuropeptide somatostatin is widely distributed in the central nervous system and in peripheral tissues and may be involved in the regulation of a number of physiological functions including movement and cognition. Somatostatin may also have a role in the development of the central nervous system, in particular, the cerebellum and spinal cord. Somatostatin induces its actions by interacting with a family of membrane associated receptors. Recently, five somatostatin receptors have been cloned and referred to as SSTR1-SSTR5. The distribution of the expression of the mRNAs for these receptors are distinct but overlapping. Preliminary pharmacological analysis of these receptors may lead to the development of selective ligands at these receptors. These compounds may be useful in identifying the selective functions of these receptor subtypes. Some somatostatin analogues have antiproliferative actions and are used presently to treat carcinoids. Development of subtype selective somatostatin analogues could be helpful in further identifying somatostatin receptor-expressing tumors and in the treatment of cancer. The cloning of these receptors has now opened up the possibility of more clearly investigating the functions of somatostatin in the brain and peripheral tissues and will facilitate the generation of new somatostatin drugs that may be employed for the treatment of a number of diseases.
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PMID:Molecular properties of somatostatin receptors. 767 4

Somatostatin regulates endocrine and exocrine secretion, acts as a neurotransmitter/neuro-modulator and possesses antiproliferative properties. These diverse physiological effects are mediated by G-protein coupled receptors of which at least five subtypes have been cloned (SSTR1-5). Here, we have investigated the tissue distribution pattern of mRNAs encoding the five SRIF receptor subtypes in the adult rat by RT-PCR analysis and in situ hybridization histochemistry. All five receptor subtypes were found to be expressed simultaneously in brain and pituitary by RT-PCR. Besides, the in situ hybridization results clearly show a distinct but overlapping expression pattern of SSTR1-5 mRNA in the central nervous system as was found by RT-PCR for the periphery. Such distinct SRIF receptor expression may contribute to the selective biological functions of the receptor subtypes.
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PMID:Differential expression of five somatostatin receptor subtypes, SSTR1-5, in the CNS and peripheral tissue. 769 37

Somatostatin (SRIF) exerts its diverse biological effects through a family of membrane receptors. In addition to inhibiting GH secretion, SRIF has antiproliferative effects and has been used clinically in the treatment of pituitary tumors. SRIF receptor (SSTR) expression has recently been identified in pituitary adenomas, and it is unknown whether differential expression of SSTR subtypes predicts clinical responses to SRIF analogs. We therefore determined which SSTR subtype messenger RNAs (mRNAs) are expressed in pituitary adenoma phenotypes and in normal human pituitary tissue using reverse transcriptase-polymerase chain reaction and tested whether expression of specific SSTR subtype mRNA is necessary for SRIF inhibition of GH secretion in human somatotroph adenomas in vitro. Expression of SSTR subtypes 1, 2, and 5 mRNA was identified in all pituitary adenoma types and normal pituitary tissue. In contrast, SSTR3 mRNA was detected in only one somatotroph adenoma as well as in control insulinoma tissue, a tissue known to express SSTR3 mRNA, and was not detected in normal pituitary tissue. SSTR4 mRNA was not detected in any human pituitary tissue. To determine whether specific SSTR subtype mRNA expression is required for SRIF inhibition of GH secretion, five somatotroph adenomas were treated with 10(-7) mol/L SRIF in vitro, and significant inhibition of GH release occurred in all adenomas. All five tumors expressed SSTR2 mRNA and SSTR5 mRNA, and three expressed SSTR1 mRNA. The absence of SSTR1 mRNA expression did not affect the ability of SRIF to suppress GH secretion. We conclude that: 1) human pituitary adenomas and normal pituitary express multiple SSTR gene transcripts; 2) SSTR5 mRNA, which has not been reported in other human endocrine tumor types, is expressed in neoplastic and normal pituitary tissue; and 3) SSTR2 mRNA, SSTR5 mRNA, and variable SSTR1 mRNA are expressed in GH-secreting tumors, which are responsive to SRIF in vitro. Further understanding of SSTR gene expression in pituitary adenomas will facilitate our understanding of the pathogenetic mechanisms of tumorigenesis and may provide a rationale for the use of specific SRIF analogs for clinical application.
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PMID:Somatostatin receptor subtype gene expression in pituitary adenomas. 771 15

At least five different types of somatostatin receptors (SSTRs): SSTR1-5 have been recently cloned. Here, we report the distribution of somatostatin receptor 3 (SSTR3) mRNA in spinal cord and spinal ganglia by in situ hybridization. We demonstrate the presence of this transcript in motorneurones of the spinal cord and other motor nuclei of the brain stem, and in the sensory neurones of the spinal ganglia. These data suggest a role for SSTR3 in motor and sensory functions.
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PMID:Expression of somatostatin receptor 3 mRNA in the motorneurones of the rat spinal cord, and the sensory neurones of the spinal ganglia. 776 96

The neuropeptide somatostatin is the major physiological inhibitor of growth hormone secretion. With the aim of identifying the receptor subtypes through which this neuropeptide may be exerting its neuroendocrine actions in the brain, we have examined by in situ hybridization the distribution of the messenger RNA for SSTR1 and SSTR2 isoforms in the hypothalamus of adult male and female rats. Both receptor subtypes were highly expressed in the medial preoptic area, suprachiasmatic nucleus and arcuate nucleus. High SSTR1, but low SSTR2, expression was evident in the para- and periventricular nuclei as well as in the ventral premammillary nucleus. Conversely, moderate to high SSTR2, but low SSTR1, messenger RNA levels were detected in the anterior hypothalamic nucleus, ventromedial and dorsomedial nuclei and medial tuberal nucleus. Taken together, these distributional patterns conform to those of somatostatin binding sites as visualized by in vitro autoradiography, suggesting that an important proportion of SSTR1 and SSTR2 receptors in the hypothalamus are associated with the perikarya and dendrites of intrinsic neurons. The distribution of SSTR1-expressing cells within the periventricular, paraventricular and suprachiasmatic nuclei was similar to that of neurons previously reported to contain and/or express somatostatin in the brain suggesting that some of the SSTR1 receptors may correspond to autoreceptors. Within the arcuate nucleus, the distribution of SSTR1 and SSTR2 messenger RNA-expressing cells was comparable to that of neurons previously found to selectively bind somatostatin-14 within this area. Given that over one third of these cells also contain and express growth hormone-releasing factor, the present findings suggest that both of these receptor subtypes are involved in the central regulation of growth hormone-releasing factor secretion by somatostatin. Taken together, the present results suggest that SSTR1 and SSTR2 somatostatin receptor messenger RNAs are heavily expressed in those neurons containing somatostatin and/or growth hormone-releasing factor and thereby imply a role for both SSTR1 and SSTR2 somatostatin receptor subtypes in neuroendocrine regulation of growth hormone secretion in both sexes of this species.
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PMID:Patterns of expression of SSTR1 and SSTR2 somatostatin receptor subtypes in the hypothalamus of the adult rat: relationship to neuroendocrine function. 777 68

Four of the five somatostatin receptor (SSTR) subtypes bind the two native forms of somatostatin, i.e., somatostatin-14 (S-14) and amino-terminally extended somatostatin-28 (S-28), with comparable affinities (approximately 0.2 nM). The SSTR5 subtype exhibits 10-50-fold higher affinity for S-28 than for S-14 (0.2 and 5 nM, respectively). To determine which domains in SSTR5 are responsible for the observed pharmacological selectivity, a series of SSTR2/SSTR5 chimeras were constructed and expressed in Chinese hamster ovary cells. Saturation and competition radioligand binding studies demonstrated that the region encompassing transmembrane domain 6 (TM6) through the carboxyl terminus plays a critical role in the lower binding affinity of S-14 for SSTR5. Substitution of this region with the corresponding region of SSTR2 produced chimeric receptors with high affinity for both S-28 and S-14. Examination of amino acid sequences revealed both a specific conserved hydrophobic residue and a conserved tyrosine in TM6 of SSTR1-4. At comparable positions in SSTR5, these residues are glycine (G258) and phenylalanine (F265), respectively. Substitution of G258 with phenylalanine did not alter the preference of SSTR5 for S-28 over S-14. However, substitution of F265 with tyrosine increased the binding affinity of S-14 by 20-fold, to an affinity comparable to that observed for the SSTR2 subtype. These data indicate that replacement of phenylalanine with tyrosine at position 265 in SSTR5 can modify ligand binding selectivity and abolish the preference for S-28 over S-14. This finding suggests that the tyrosine in the predicted TM6 may be an important contact point between somatostatin and SSTR.
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PMID:A single amino acid substitution in somatostatin receptor subtype 5 increases affinity for somatostatin-14. 783 36

Somatostatin is a potent inhibitor of gastric acid secretion. Recently, at least five distinct somatostatin receptor subtypes (SSTR) have been characterized and evaluated using relatively selective peptide analogues of somatostatin. We sought to determine which somatostatin receptor subtypes are involved in peripheral regulation of gastric acid secretion. Fasted, male Sprague-Dawley rats were anesthetized and were implanted with a double-lumen cannula in the stomach. Acid secretion was measured in gastric samples collected every 10 min by backtitration to pH 7. After a 30-min basal period, a 2-h intravenous infusion of pentagastrin (24 micrograms.kg-1.h-1 i.v.) was started. During the second pentagastrin hour, a 1-h intravenous infusion of either vehicle (0.1% canine serum albumin in 0.9% saline) or somatostatin receptor agonists was begun. The somatostatin receptor agonists included peptides with relative specificity for SSTR1-5 (somatostatin-14; 10 nmol.kg-1.h-1); SSTR2, SSTR3, and SSTR5 [SMS-(201-995); 10 nmol.kg-1.h-1]; SSTR2 (1-1,000 nmol.kg-1.h-1); SSTR3 (10-1,000 nmol.kg-1.h-1); and SSTR5 (10-1,000 nmol.kg-1.h-1). The SSTR2 agonist decreased pentagastrin-stimulated acid secretion dose dependently, from 82 +/- 7% of maximum acid output at 1 nmol.kg-1.h-1 to 4 +/- 7% of maximum at 100 nmol.kg-1.h-1. At 10 nmol.kg-1.h-1, the SSTR2 agonist inhibited acid secretion (40 +/- 7% of maximum) similarly to somatostatin (37 +/- 4% of maximum) and SMS-(201-995) (31 +/- 4% of maximum). The SSTR2 agonist inhibited acid secretion approximately 10- to 100-fold more potently than either the SSTR3 or the SSTR5 agonist. These results indicate that somatostatin regulates gastric acid secretion by activation of SSTR2 receptors.
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PMID:Activation of somatostatin receptor subtype 2 inhibits acid secretion in rats. 784 Jan 90

Somatostatin receptors are abundantly expressed on a variety of human endocrine and epithelial tumors. The ability of these receptors to couple to effector pathways that inhibit the growth of these tumor cells has prompted the use of somatostatin agonists in the treatment of human neoplasms. It has been demonstrated that somatostatin stimulates a phosphotyrosine phosphatase in human tumor cells through a receptor-mediated process. This stimulation may counteract the growth-promoting properties of growth factors and the receptor tyrosine kinases that they activate. The recent cloning and characterization of distinct somatostatin receptor subtypes raise the possibility that different receptor subtypes mediate distinct effector pathways. To determine whether cloned somatostatin receptors could mediate coupling to phosphotyrosine phosphotyrosine phosphatase activity, we examined phosphatase activity after somatotostatin activation of the rat somatostatin receptors SSTR1 and SSTR2 after their stable expression in heterologous Chinese Hamster Ovary (CHO-K1) cells. We found that stimulation of SSTR1 cells was capable of increasing phosphotyrosine phosphatase activity, despite the coupling of both receptors to the inhibition of adenylyl cyclase in these cells. This activation was characterized by an EC50 of 70 nM and was sensitive to pertussis toxin. In addition, we demonstrate that activation of phosphotyrosine phosphatase activity in pituitary cell lines correlates with the endogenous expression of the SSTR1 gene within these cells.
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PMID:The somatostatin receptor SSTR1 is coupled to phosphotyrosine phosphatase activity in CHO-K1 cells. 785 46


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