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)

In this study sequence-specific antisense oligonucleotide probes have been used to investigate the distribution of the mRNAs coding for the somatostatin receptor subtypes termed somatostatin receptor 1, somatostatin receptor 2 and somatostatin receptor 3 in the rat brain and pituitary using in situ hybridization techniques. The three receptor subtype mRNAs were found to be widely distributed in the brain with different patterns of expression, but with some overlap. Somatostatin receptor 1 mRNA was particularly concentrated in the cerebral and piriform cortex, magnocellular preoptic nucleus, hypothalamus, amygdala, hippocampus, and several nuclei of the brainstem. Somatostatin receptor 3 mRNA was very abundant in the cerebellum and pituitary (in contrast to somatostatin receptor 1), but it was also found in hippocampus, amygdala, hypothalamus and in motor nuclei of the brainstem. Somatostatin receptor 2 mRNA levels were very low relative to the other two mRNAs evaluated. Receptor 2 mRNA was observed in the anterior pituitary, and in the brain it was found in the medial habenular nucleus, claustrum, endopiriform nucleus, hippocampus some amygdala nuclei, cerebral cortex and hypothalamus. None of the three somatostatin receptor mRNAs studied here was found in the caudate nucleus. Northern analysis revealed distinct sizes of mRNAs for each subtype, and displacement experiments showed that each probe sequence was subtype-specific.
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PMID:Distribution of somatostatin receptors 1, 2 and 3 mRNA in rat brain and pituitary. 770 98

Somatostatin (SRIF) SS-2 binding sites were originally defined in rat brain cerebral cortex membranes using [125I]Tyr11-SRIF-14 in the presence of 120 mM NaCl. These sites were characterized by their high affinity for SRIF-14 and SRIF-28, but very low affinity for cyclic peptides such as octreotide (SMS 201-995) and seglitide (MK 678). The characteristics of SS-2 sites are reminiscent of 125I]CGP 23996-labelled sites in rat brain which have been termed SRIF-2 sites. In the present study, the pharmacological profile of SS-2 sites was determined in radioligand binding studies performed in rat cortex membranes using [125I]SRIF-14 in the presence of 120 mM NaCl and compared to that of human SSTR-1 receptors expressed in human embryonic kidney (HEK 293) cells, using [125I]SRIF-14. The rank orders of affinity of a variety of SRIF analogues and synthetic peptides for SS-2 binding sites and recombinant human SSTR-1 receptors were very similar and correlated highly significantly (r = 0.99). However, SS-2 binding correlated also with binding to recombinant SSTR-4 receptors (r = 0.91). Autoradiographic studies were performed using the radioligand [125I]CGP 23996 which has been claimed to label selectively SRIF-2 binding sites and compared with the distribution of SSTR-1 receptor mRNA determined using in situ hybridization in rat brain. Although some overlap was observed between the distribution of SSTR-1 mRNA and [125I]CGP 23996 binding sites, the latter were clearly more widespread, suggesting this ligand to label SSTR-1 and other sites. In addition, inhibition of forskolin-stimulated adenylate cyclase was investigated in HEK 293 cells transfected with human SSTR-1 receptors; a variety of SRIF analogues and short synthetic peptides behaved as agonists at adenylate cyclase and displayed a rank order of potency highly similar to that observed for these compounds at SS-2 binding sites. Seglitide acted as an antagonist at SSTR-1 receptor mediated inhibition of adenylate cyclase activity with a pKB of 4.42. It is concluded that the pharmacological profile of SS-2 binding sites resembles most closely that of SSTR-1 receptors (although similarities with SSTR-4 receptors were observed), that [125I]CGP 23996 labels presumably several SRIF receptors in rat brain, and that SSTR-1 receptors are negatively and efficiently coupled to adenylate cyclase activity.
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PMID:Pharmacological identity between somatostatin SS-2 binding sites and SSTR-1 receptors. 778 6

Somatostatin (SRIF) SS-1 binding sites were initially defined in radioligand binding studies performed in rat brain cerebral cortex membranes using [125I]204-090 (a radiolabelled Tyr3 analogue of SMS 201-995, octreotide). SRIF-1 recognition sites were defined in binding studies performed with [125I]MK 678 (seglitide). Both SS-1 and SRIF-1 sites were characterized by their high affinity for SRIF-14, SRIF-28 and for cyclic peptides such as octreotide and seglitide, in marked contrast to SS-2 and SRIF-2 sites which have very low affinity for these synthetic SRIF analogues. In the present study, SS-1 and SRIF-1 radioligand binding studies were performed in rat cortex membranes and compared to results obtained in cloned Chinese hamster ovary cells expressing human SSTR-2 receptors using [125I]204-090 and/or [125I]MK-678. The rank orders of affinity of a variety of SRIF analogues and synthetic peptides for SS-1/SRIF-1 binding sites and recombinant SSTR-2 receptors were very similar and correlated highly significantly (r = 0.94-0.99); by contrast, correlation between SS-1 and SSTR-5 (r = 0.44) or SSTR-3 binding (r = 0.07) was not significant. Autoradiographic studies were performed in rat brain using both radioligands [125I]204-090 and [125I]MK-678 and compared with the distribution of SSTR-2 receptor mRNA determined using in situ hybridization. A clear overlap was observed between the distribution of SSTR-2 mRNA and binding sites labelled with both radioligands. SSTR-2 receptor-mediated inhibition of forskolin-stimulated adenylate cyclase in Chinese hamster ovary cells by a variety of SRIF analogues and short synthetic peptides displayed a rank order of potency highly similar to their rank order of affinity at SS-1/SRIF-1 binding sites. It is concluded that SS-1 and SRIF-1 binding sites respectively labelled with [125I]204-090 and [125I]MK 678, both display the pharmacological profile of SSTR-2 receptors, that the distribution of [125I]204-090 and [125I]MK-678 binding sites in rat brain is superimposable and largely comparable to that of SSTR-2 mRNA expression. It is also shown that neither [125I]204-090 nor [125I]MK-678 label SSTR-3 or SSTR-5 receptors in rat brain. Finally, it is demonstrated that SSTR-2 receptors can very efficiently couple to adenylate cyclase activity in an inhibitory manner.
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PMID:Characterization and distribution of somatostatin SS-1 and SRIF-1 binding sites in rat brain: identity with SSTR-2 receptors. 778 7

The relative abundances of mRNAs encoding four different somatostatin receptors were examined using PCR techniques during postnatal development of the rat brain and hypophysis. In most tissues, somatostatin receptor 1 and 4 mRNAs are more abundant than those encoding somatostatin receptor 2 and 3. Transcript levels of somatostatin receptor subtype 4 are relatively high in the cortex, hippocampus, and striatum, those of subtype 1 in the cortex and brainstem, and those of subtype 3 in the cerebellum. In situ hybridization revealed the presence of significant amounts of somatostatin receptor 1 mRNA, as early as prenatal day 14, in the trigeminal ganglion and in the neuroepithelial layers surrounding the lateral, third, and fourth ventricles. In the developing cortex a morphological change in the sites of somatostatin receptor 1 gene expression occurs; mRNA is present superficially in the cortex at prenatal stages, appears in all layers shortly after birth, and in adult rats is restricted to the deep cortical layers. In the cerebellum, somatostatin receptor 1 mRNA levels are highest around birth, declining thereafter. In contrast, cerebellar somatostatin receptor 3 transcripts are absent at birth, become detectable around postnatal day 7, and reach a maximal level during maturation.
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PMID:Expression patterns of rat somatostatin receptor genes in pre- and postnatal brain and pituitary. 837 6

To characterize the nature and distribution of somatostatin (SRIF) receptors, radioligand binding studies and in vitro receptor autoradiography were performed in Rhesus monkey brain using either [125I]LTT-SRIF-28 ([Leu8, D-Trp22, 125I-Tyr25]SRIF-28) alone or in the presence of 3 nM seglitide (to block sst2 sites), [125I]Tyr3-octreotide or [125I]CGP 23996 (c[Asu-Lys-Asn-Phe-Trp-Lys-Thr-Tyr-Thr-Ser]) in buffer containing either 120 mM Na+ or 5 mM Mg2+. [125I]Tyr3 -octreotide labelled an apparently homogeneous population of sites in cerebral and cerebellar cortex (Bmax = 27.3 +/- 2.8 fmol/mg protein and 52.6 +/- 8.6 fmol/mg protein, PKd = 9.46 +/- 0.03 and] 9.93 +/- 0.03, respectively). The pharmacological profile of these sites correlated highly significantly with that of human recombinant sst2 receptors (r = 0.996), but not or much less with that of human recombinant sst3 and sst5 receptors (r = 0.12 and 0.45, respectively). [125I]CGP 23996 (in Na(+)-buffer) also labelled an apparently homogeneous population of sites in Rhesus monkey cerebral cortex membranes (Bmax = 3.1 +/- 0.3 fmol/mg protein, pKd = 10.57 +/- 0.08), the pharmacological profile of which was highly significantly correlated with the profiles of human recombinant sst1 and sst4 receptors (r = 0.98 and 0.96, respectively). Using receptor autoradiography, high levels of [125I]LTT-SRIF-28 and [125I]Tyr3 -octreotide recognition sites were found in basal ganglia, molecular and granular layers of the cerebellum and layers III, V and VI of entorhinal cortex. In these regions, the addition of 3 nM seglitide produced a marked decrease of [125I]LTT-SRIF-28 binding. Low levels of [125I]LTT-SRIF-28 binding were observed in subiculum, pituitary and choroid plexus. By contrast, [125I]CGP 23996 labelling in the presence of Mg2+ as well as Na+ ions was highest in pituitary and choroid plexus. However, [125I]CGP 23996 binding was diversely affected by these ionic conditions in several regions of hippocampus and cerebral cortex. Displacement of [125I]CGP 23996 (in Mg(2+)-buffer) with seglitide in the molecular layer of the cerebellum, deep layers of the entorhinal cortex, layers I, II and V of the insular cortex and frontal pole yielded complex competition curves suggesting the presence of two populations of SRIF receptors. By contrast, [125I]CGP 23996 binding (in Mg(2+)-buffer) in the choroid plexus, hilus of the dentate gyrus and stratum oriens and radiatum of the CA3 field of hippocampus was not affected by seglitide up to 10 microM, suggesting only sst1 and/or sst4 sites which have a negligible affinity for seglitide to be present in these structures. Taken together, these results suggest that [125I]CGP 23996 (in the presence of Na+) labels exclusively SRIF-2 receptors (sst1 and/or sst4), whereas in the presence of Mg2+ ions, [125I]CGP 23996 labels both SRIF-2 and SRIF-1 receptors (sst2, sst3 and sst5). The present study also demonstrates the presence and differential distribution of sst2 and sst1/sst4 receptors in the Rhesus monkey brain.
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PMID:Somatostatin receptors in the rhesus monkey brain: localization and pharmacological characterization. 873 98

Effector coupling of somatostatin receptor subtypes sst1 and sst2 was examined in a reconstituted system. Forskolin-stimulated cyclic adenosine monophosphate (cAMP) formation was inhibited 66% by somatostatin (SRIF-14) in CHO cells expressing somatostatin receptor 1(sst1) (CHO-SR1), but not sst2, in a dose-dependent manner with an ED50 of 1 x 10(-9) mol/L SRIF-14. The inhibition was blocked by pertussis toxin (PTX), indicating that sst1 is coupled to adenylyl cyclase via PTX-sensitive Gi protein. In CHO cells, Gi alpha 2 and Gi alpha 3 mRNAs were detected. In adenylyl cyclase assays, 1 mumol/L SRIF-14 caused a 16% inhibition of forskolin-stimulated adenyly cyclase activity. Preincubation with Gi alpha 3, but not Gi alpha 1/Gi alpha 2, antiserum blocked this inhibition. By contrast, sst2 is coupled to adenylyl cyclase via Gi alpha 1. In cells expressing sst2 with Gi alpha 1(CHO-SR2G1), SRIF-14 significantly inhibited forskolin-stimulated cAMP formation by 53% and with an ED50 at 4 x 10(-9)mmol/L SRIF-14, which was completely blocked by PTX; ED50 values for sst1 and sst2 agree with the IC50 values in binding assays. In CHO-SR1, the rank of potency of agonists affecting adenyl cyclase was SRIF-14 = SRIF-28 > RC 160 > SMS 201-995. In CHO-SR2G1, the rank was RC-160 > SRIF-14 = SRIF-28 > SMS 201-995.
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PMID:Effector coupling of somatostatin receptor subtypes on human endocrine tumors. 876 78

Somatostatin (SRIF) receptor subtypes (sst) were characterized in hypothalamic neurons and astrocytes by quantitative reverse transcription-polymerase chain reaction and radioreceptor assays using [125I-Tyr0,D-Trp8]SRIF-14 as a ligand in ionic conditions discriminating between SRIF-1 (sst2, -3, and -5 receptors) and SRIF-2 (sst1 and -4 receptors) binding sites. In neurons, sstl mRNA levels were twofold higher than those of sst2, and sst3-5 expression was only minor. Astrocytes expressed 10-fold less sst mRNAs than neurons, which corresponded mostly (80%) to sst2. SRIF-1 binding site radioautography indicated that 10% of hypothalamic neurons were labelled on both cell bodies and neuritic processes, as were 35% of astrocytes. On neuronal and glial membranes, SRIF-14 and octreotide, an sst2/sst3/sst5-selective analogue, completely displaced SRIF-1 binding, whereas des-AA(1,2,5)[D-Trp8,IAmp9]SRIF (CH-275), an sst1-selective analogue, was ineffective. Using SRIF-2 conditions, only SRIF-14 and CH-275 displaced the binding on neurons. No SRIF-2 binding was observed on glia. SRIF-14 and octreotide inhibited forskolin-stimulated adenylyl cyclase activity in neurons and glia, whereas CH-275 was effective in neurons only. In patch-clamp experiments, SRIF-14 modulated the glutamate sensitivity of hypothalamic neurons with either synergistic or antagonistic effects; CH-275 was only stimulatory and octreotide inhibitory. It is concluded that hypothalamic neurons express primarily sst1 and sst2, sst2 predominates in astrocytes, and both receptors induce distinct biological effects.
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PMID:Distinct patterns of expression and physiological effects of sst1 and sst2 receptor subtypes in mouse hypothalamic neurons and astrocytes in culture. 916 19

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

Radioimaging of various human tumours by means of somatostatin analogues and vasoactive intestinal peptide has been introduced into clinical practice in recent years. The finding that human tumours express various subtypes of somatostatin receptors has led to the development and characterization of a novel peptide tracer, termed MAURITIUS. MAURITIUS identifies a broad range of somatostatin receptors with high binding affinity, and somatostatin receptor 1 with low binding affinity. In order to evaluate patients for tumour radiotherapy with 90Y-MAURITIUS, tumour dose calculation is performed with 111In-MAURITIUS [111In-DOTA-lanreotide]. Treatment is initiated in patients presenting a tumour uptake of > or = 10 Gy/GBq (i.e., standard dose for 1 treatment cycle with 90Y-MAURITIUS). In 25 patients with advanced cancer refractory to conventional antineoplastic treatment 111In-MAURITIUS (approximately 150 MBq; 10 nmol/patient), scintigraphy and dosimetry was performed. Dosimetry data were calculated based on scintigraphic results as well as urine, faeces and blood data. In all patients, at least one tumour site was visualized during the initial few minutes of application. Additional tumour sites not seen on conventional imaging (computerized tomography, magnetic resonance imaging bone scan) could be detected in 6 patients with carcinoids, one patient with prostate cancer and one patient with lymphoma. Liver metastases were visualized in all patients with gastrointestinal cancers, while the primary tumour was not detected in 2 patients with pancreatic, and in 1 patient with rectal, cancer. The calculated radiation dose for tumours and/or metastases ranged between 3-60 Gy/GBq for 90Y-MAURITIUS. MAURITIUS is a universal receptor ligand for a large variety of different human tumours, and is suitable for treatment when labelled with 90Y.
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PMID:"MAURITIUS": tumour dose in patients with advanced carcinoma. 1060 37

The peptide hormone somatostatin inhibits the release of insulin. The gene encoding somatostatin receptor 1 is expressed in pancreatic beta-cells and insulinoma RIN 1046-38 cells. In the present study the mechanisms underlying the regulation of the somatostatin receptor 1 gene in pancreatic beta-cells were investigated. Transient transfections of RIN 1046-38 cells with promoter/reporter gene constructs and footprint analysis revealed two regions, fp1 and fp2, that were necessary for the observed promoter activity. Mutagenesis of the fp2 region delineated the cis-acting element to the motif 5'-TTAATCATT-3'. The POU domain transcription factor Tst-1 was identified as trans-activator mediating the 5'-TTAATCATT-3' motif-dependent transcription in RIN 1046-38 cells and heterologous CV1 cells. Tst-1, known as a transcriptional regulator in keratinocytes, glial cells, and neurons, has been detected by immunohistochemistry in pancreatic islets. Altogether, we demonstrate Tst-1 as transcriptional regulator in pancreatic neuroendocrine cells.
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PMID:The POU domain transcription factor Tst-1 activates somatostatin receptor 1 gene expression in pancreatic beta -cells. 1086 97


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