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)

We previously reported the cloning of two distinct somatostatin receptor (SSTR) subtypes, SSTR1 and SSTR2. Although both SSTR1 and SSTR2 bound somatostatin specifically and with high affinity, neither was coupled to adenylyl cyclase, a major cellular effector of somatostatin's actions. Here we report the cloning and functional characterization of a third member of the SSTR family. Human SSTR3 is a protein of 418 amino acids and has 45% and 46% identity with human SSTR1 and SSTR2, respectively. RNA blotting studies showed that SSTR3 mRNA could be readily detected in brain and pancreatic islets. The pharmacological properties of human SSTR3 were characterized by transiently expressing the human SSTR3 gene in COS-1 cells. Membranes from cells expressing human SSTR3 bound the somatostatin agonist [125I]CGP 23996 specifically and with high affinity, with a rank order of potency of somatostatin-28 = CGP 23996 > somatostatin-14 > SMS-201-995. Studies using cells transiently coexpressing the human dopamine D1 receptor and human SSTR3 showed that somatostatin was able to inhibit dopamine-stimulated cAMP formation in a dose-dependent manner, indicating that SSTR3 was functionally coupled to adenylyl cyclase. These results indicate that the diverse biological effects of somatostatin are mediated by a family of receptor with distinct, but overlapping, tissue distributions, unique pharmacological properties, and potentially different functions.
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PMID:Somatostatin receptors, an expanding gene family: cloning and functional characterization of human SSTR3, a protein coupled to adenylyl cyclase. 133 45

1. The effect of the long-acting somatostatin analogue SMS-201995 on diabetes control was assessed in 6 insulin-dependent diabetic patients (3 men and 3 women aged 19-38 years). 2. Plasma glucose and triglyceride profiles were obtained on 4 consecutive days, from 8:00 a.m. to 2:00 p.m. On the first 2 days the patients received their usual dose of insulin and ate at 8:00 a.m. and at noon. On the third and fourth days they received 1/3 of their usual insulin dose together with 100 micrograms SMS-201995 injected subcutaneously. 3. Postprandial glucose and triglyceride increases were blunted during the 360 min of observation on both days after SMS-201995 administration. The areas under the glucose-time plots fell from 23.72 +/- 12.29 (mean +/- SD) to 7.98 +/- 14.26 (P < 0.05) and the areas under the triglyceride-time plots from 10.51 +/- 9.01 to -3.15 +/- 4.30 g.min.dl-1 (P < 0.01). 4. No adverse reactions were observed after SMS-201995 administration for 2 days. 5. We conclude that administration of the somatostatin analogue SMS-201995 may be beneficial for insulin-dependent diabetic patients.
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PMID:Acute effect of the somatostatin analogue SMS-201995 on plasma glucose and triglycerides in insulin-dependent diabetic patients. 134 35

We have identified specific receptors for somatostatin (SS) in the rabbit retina using the radioligand [125I]Tyr11-Somatostatin. [125I]Tyr11-SS bound with high affinity to retinal membranes as was ascertained by both kinetic and saturation experiments. Scatchard analysis of the saturation data for [125I]Tyr11-SS binding to retinal membranes suggest a single population of sites with an apparent affinity constant (KD) of 0.90 +/- 0.20 nM and a maximum number of binding sites (Bmax) of 104 +/- 52 fmol/mg protein. The specific binding of [125I]Tyr11-SS was displaced in a dose-dependent manner by SS, Tyr11-SS, SMS 201-995, SS-28 and D-Trp8-SS. The inactive SS analog SS28(1-14) as well as the peptides CRF and bombesin had no effect. In addition, the specific binding of [125I]Tyr11-SS was attenuated by GTPgS. These findings demonstrate the presence of a selective receptor for SS in the rabbit retina that is coupled to guanine nucleotide binding protein(s).
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PMID:Characterization of [125I]Tyr11-somatostatin binding sites in the rabbit retina. 134 15

Pharmacological studies have suggested that the somatostatin (SS) receptor is heterogeneous and may exhibit subtypes selective for SS-14 and SS-28. Whether this heterogeneity can be explained by separate molecular forms of the receptor protein is unclear. In the present study, we have developed a novel photosensitive azido derivative of the octapeptide SS analog Tyr3 SMS (EE 581) and used it as a photoaffinity probe to characterize the molecular components of the SS receptor in five receptor positive tissues (normal rat brain, pituitary, pancreas, and adrenal cortex, and mouse AtT-20 pituitary tumor cells). [125I]EE-581 labeled specific high affinity binding sites in all these tissues (Kd range 1.3-1.67 nM). Photoaffinity labeled membrane SS receptors were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by autoradiography. Three specifically labeled SS receptor proteins of 80 kilodaltons (kDa), 58 kDa, and 32 kDa were identified and exhibited a tissue-specific distribution. The 58 kDa species was the exclusive form in pancreas, adrenal cortex, and AtT-20 cells and the dominant form in brain. The 32 kDa receptor protein was expressed as a minor form (ratio of 58 kDa:32 kDa 3:1), exclusively in brain. The 80 kDa receptor was found only in the pituitary where it occurred as the sole SS receptor species. Competition experiments showed that the 58 kDa and 32 kDa receptor proteins in brain reacted with SS-14 greater than SS-28; in contrast, the 58 kDa protein in AtT-20 cells bound SS-28 greater than SS-14 suggesting the existence of distinct subtypes of the 58 kDa receptor in these two tissues. These data represent the first systematic evaluation of the molecular forms of SS receptor proteins by photoaffinity labeling in different target tissues and provide direct evidence for molecular heterogeneity and SS-14/SS-28 selectivity; a major 58 kDa protein present in most tissues, an additional 32 kDa protein uniquely expressed in brain, and an 80 kDa protein exclusive to the normal pituitary.
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PMID:Photoaffinity labeling of the somatostatin receptor: identification of molecular subtypes. 134 80

Therapeutic efficacy of a synthetic somatostatin analogue for the treatment of carcinoid tumors is still controversial. In vivo studies performed in our laboratory showed that a somatostatin analogue, SMS 201-995, significantly inhibited growth of human pancreatic carcinoid (BON) tumors xenotransplanted into athymic nude mice. In the present study, however, SMS 201-995 did not inhibit in vitro growth of BON cells, but rather SMS 201-995 stimulated growth in a dose-dependent fashion. The growth-stimulatory effect was likely mediated through the reduction of cyclic AMP production. Unsuccessful treatment of certain types of carcinoid tumor with SMS 201-995 may be partly due to the direct growth-stimulatory effect of SMS 201-995 on carcinoid cells.
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PMID:Unexpected growth-stimulatory effect of somatostatin analogue on cultured human pancreatic carcinoid cells. 135 20

The insulin-, glucagon-, and somatostatin-producing cells in the pancreatic islets derive from a common precursor stem cell and differentiate sequentially during embryonic development, thereby providing an informative model for the study of the transcriptional mechanisms involved in the control of cell-specific gene expression. Relative to the early expression of the glucagon and insulin genes on embryonic days 10 and 12, respectively, the expression of the somatostatin gene is delayed (day 17). The relatively late expression of the somatostatin gene indicates the involvement of both negative and positive transcriptional control mechanisms. We show that the expression of the somatostatin gene in pancreatic islet cells is accomplished by the interplay of both positive and negative cis-regulatory DNA elements. We have characterized the functional properties of one of these positive control elements, the somatostatin gene upstream enhancer element (SMS-UE). The SMS-UE is a pancreatic islet D-cell-specific transcriptional regulator that acts synergistically with the cyclic AMP response element. Mutation-expression and cell-free transcription analyses show that the SMS-UE is a bipartite element with two interdependent functional domains. Our results indicate that the SMS-UE is part of a functional unit that includes other transcriptional control elements of the somatostatin gene proximal promoter, and that they act together to regulate the D-cell-specific transcription of the somatostatin gene in the islet cells of the pancreas.
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PMID:Somatostatin gene transcription regulated by a bipartite pancreatic islet D-cell-specific enhancer coupled synergetically to a cAMP response element. 135 91

The expression of the genes encoding the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide in the endocrine islets of the pancreas is regulated in a cell-specific manner, defining four distinct cellular phenotypes (A-, B-, D-, and F-cells, respectively). Binding of nuclear proteins to cognate DNA sequences within cis-acting regulatory elements mediates the transcriptional events that result in the cell-specific activation or repression of gene expression. In a parallel study, we describe the functional properties of the SMS-UE, a pancreatic islet D-cell specific enhancer element that regulates the expression of the somatostatin gene and contains two interdependent domains, A and B. In the studies described herein, we have characterized the nuclear proteins that recognize the SMS-UE. Domain A of the SMS-UE is a DNA enhancer sequence that is identical to that bound by the ubiquitously distributed CCAAT box-binding protein alpha-CBF, a transcription factor that regulates the expression of the human chorionic gonadotrophin alpha-subunit gene. The B-domain, on the other hand, binds an islet cell-specific protein with characteristics similar to those of Isl-1, a transcriptional activator protein that binds to the E2 enhancer of the rat insulin-1 gene. In addition, the SMS-UE binds transcription factor CREB but not CREM, the close homolog of CREB, on a site adjacent to, or overlapping, the 3' end of domain B. We show that the carboxyl-terminal bZIP domain of CREB binds to the cAMP response element of the somatostatin gene but is not sufficient for binding to the SMS-UE, and we present evidence suggesting that CREB.SMS-UE binding requires stabilization by a region of the protein located within the transactivation domain.
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PMID:Somatostatin gene upstream enhancer element activated by a protein complex consisting of CREB, Isl-1-like, and alpha-CBF-like transcription factors. 135 92

The ontogeny of somatostatin receptors (SRIF-R) was studied in the human cerebellum from mid-gestation to the 15th month postnatal. The brains were collected 3-26 h after death, from 18 fetuses and infants, and from 4 adults aged from 48 to 82. SRIF-R were characterized by membrane-binding assay and their localization was determined by in vitro autoradiography. Both techniques were conducted with two radio-ligands: [125I-Tyr0, DTrp8]S14 and D-Phe-Cys-125I-Tyr-DTrp-Lys-Thr- ol (125I-SMS 204-090). Membrane-binding studies carried out with each radioligand showed the presence of a single population of saturable, high affinity binding sites. Neither were the Kd values for either ligand (assessed by Scatchard analysis) changed appreciably during development, mean Kd values being 0.36 +/- 0.04 nM and 0.56 +/- 0.11 nM for [125I-Tyr0,DTrp8]S14 and 125I-SMS 204-090, respectively. Although inter-individual fluctuations of the Bmax were observed, the concentration of SRIF-R in the cerebellum of fetuses and infants up to 8 months appeared to be at least 2- to 10-fold higher than in the adult cerebellum. No appreciable differences in the Bmax values were found using either radioligand. The highest density of SRIF-R was observed in the cerebellar cortex of fetuses, in particular in the external granule cell layer (EGC), where stem cells of the granule cells are generated and enter the differentiation process. A high density of SRIF-R also occurred in the internal granule cell layer.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Somatostatin receptors in the human cerebellum during development. 135 48

The ontogeny of somatostatin receptor binding was studied in developing rat retina using the iodinated derivative of the somatostatin analog, SMS 204-090. Specific binding of the ligand was seen as early embryonic day (E) 15 in the region of the inner neuroblastic layer. At E19 binding was localized to the ganglion cell and developing inner plexiform layers. At postnatal day (P) 2, there was diminished binding on autoradiography in this region. At P11, binding was more intense in the inner plexiform layer, and there was discernible binding in the outer plexiform layer. In the adult retina, the binding was seen clearly in two distinct bands corresponding to the inner plexiform layer and the outer plexiform layer. There was a single saturable binding site with the dissociation constant (Kd) of 0.25 +/- 0.04 nM. Binding sites were fairly constant throughout development except for a significant decline during the first postnatal week (Bmax = 1.8). These results demonstrate the early appearance of somatostatin receptors in the rat retina with high levels present embryologically followed by a brief decline in the early postnatal period with a return to high levels by synapse formation (P11). These receptor data parallel previous reports of the appearance of the somatostatin mRNA and peptide in rat retina.
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PMID:Developmental expression of somatostatin receptors in the rat retina. 135 17

Somatostatin (SRIF) is a neurotransmitter that produces its multiple effects in the CNS through interactions with membrane-bound receptors. Subtypes of SRIF receptors are found in the CNS that are distinguished by their sensitivities to the cyclic hexapeptide MK-678, such that SRIF1 receptors are sensitive to MK-678 and SRIF2 receptors are insensitive to MK-678. In the present study, we further examined the selectivities of a series of structurally diverse SRIF analogues for SRIF receptor subtypes. SRIF receptors were labeled by 125I-Tyr11-SRIF, which has indistinguishable affinities for SRIF receptor subtypes. The inhibition by MK-678 was incomplete, indicating this peptide is highly selective for a subtype of SRIF receptor that we have termed the SRIF1 receptor. The binding of 125I-MK-678 to SRIF1 receptors was monophasically inhibited by SRIF, the octapeptides (such as SMS-201-995), and the hexapeptides (such as MK-678), consistent with the highly selective labeling of a subtype of SRIF receptor. In contrast, the smaller CGP-23996-like analogues did not inhibit 125I-MK-678 binding to SRIF1 receptors. The binding of 125I-CGP-23996 to SRIF receptors was inhibited by SRIF and the octapeptides with Hill coefficients of less than 1, indicating that 125I-CGP-23996 labels multiple SRIF receptor subtypes. The hexapeptides and CGP-23996-like compounds produced only partial inhibitions of 125I-CGP-23996 binding, which were additive, indicating selective interactions of these compounds with the different receptor subpopulations labeled by 125I-CGP-23996. 125I-Tyr11-SRIF binding and 125I-CGP-23996 binding to SRIF receptors were likewise only partially affected by 100 microM guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S), a concentration that completely abolishes specific 125I-MK-678 binding to SRIF1 receptors. The component of 125I-CGP-23996 labeling that was sensitive to GTP gamma S was also MK-678 sensitive. Thus, two subpopulations of SRIF receptors exist in the CNS. The SRIF1 receptor is sensitive to cyclic hexapeptides such as MK-678 and to GTP gamma S but insensitive to smaller CGP-23996-like compounds. The SRIF2 receptor is sensitive to the CGP-23996-like compounds and can be selectively labeled by 125I-CGP-23996 in the presence of high concentrations of the hexapeptides or GTP gamma S because, unlike the SRIF1 receptor, the SRIF2 receptor is insensitive to these agents. The SRIF receptor subtype-selective peptide analogues will be useful in the future characterization of the functions mediated by SRIF receptor subtypes in the CNS.
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PMID:Analogues of somatostatin bind selectively to brain somatostatin receptor subtypes. 135 93


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