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 PTH2 receptor is a G protein-coupled receptor selectively activated by PTH. We are studying the receptors distribution to guide the investigation of its physiological function. We have now generated an antibody from a C-terminal peptide sequence of the PTH2 receptor and used this to study its cellular distribution. Labeling with the antibody identified a number of endocrine cells expressing the PTH2 receptor, including thyroid parafollicular cells, pancreatic islet D cells, and some gastrointestinal peptide synthesizing cells. There was complete overlap of PTH2 receptor labeling with somatostatin in pancreatic islets, and partial overlap with somatostatin in thyroid parafollicular cells and in the gastrointestinal tract. Furthermore, observations made previously by in situ hybridization histochemistry, including expression throughout the cardiovascular system, as well as by discrete populations of cells within the gastrointestinal tract and reproductive system were confirmed. These data suggest a broad role for the PTH2 receptor, especially within the endocrine system, and provide a basis for experimental exploration of its physiology.
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PMID:Distribution of the parathyroid hormone 2 receptor in rat: immunolocalization reveals expression by several endocrine cells. 1038 34

Somatostatin actions are mediated through G-protein coupled receptors named sst(1) to sst(5). We used an affinity-purified polyclonal antibody AS-69, directed against a specific N-terminal peptide sequence of sst(3) to determine the immunohistochemical distribution of the sst(3) receptor in the rat and human brain. The specificity of the antibody was shown by Western blotting experiments using an N-terminal sst(3) fusion protein. Enzymatic deglycosylation experiments were combined to blotting experiments on a sst(3)-transfected cell line and rat brain membrane proteins and with immunocytochemistry on the sst(3)-transfected cell line. These studies showed that the antibody detected the deglycosylated sst(3) receptor protein. Immunohistochemical staining showed that sst(3) immunoreactivity recognised by this N-terminal antiserum was widely distributed throughout the brain with cells and processes labelled in the cerebral cortex, regions of the limbic system (including the hippocampal formation, some amygdaloid regions, some basal ganglia nuclei and regions from the nucleus basalis complex), the habenula, the hypothalamus, the thalamus, different mesencephalic structures (substantia nigra, zona incerta, superior colliculus), the reticular formation, the cerebellum. The distribution of immunoreactivity was in good general agreement with that predicted from the localisation of sst(3) mRNA and radio-ligand binding studies; however, due to the preference of AS-69 towards the deglycosylated receptor, it appears that the sst(3) immunoreactivity detected may correspond largely to the deglycosylated receptor. This study on the immunohistochemical distribution of the sst(3) receptor in the brain may provide a better understanding of the central actions of somatotropin release-inhibiting factor (SRIF).
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PMID:Visualisation of somatostatin receptor sst(3) in the rat central nervous system. 1052 83

We investigated whether yeast signals could regulate hormone processing in mammalian cells. Chmeric genes coding for the prepro region of yeast alpha-factor and the functional hormone region of anglerfish somatostatin was expressed in rat pituitary GH(3) cells. The nascent prepro-alpha-factor-somatostatin peptides disappeared from cells with a half-life of 30 min, and about 20% of unprocessed precursors remained intracellular after a 2 h chase period. Disappearance of propeptide was insensitive to lysosomotropic agents, but was inhibited at 15 degrees C or 20 degrees C, suggesting that the hybrid propeptides were not degraded in the secretory pathway to the trans Golgi network or in lysosomes. It appeared that while most unprocessed precursors were constitutively secreted into the medium, a small portion were processed at their paired dibasic sites by prohormone-processing enzymes located in trans Golgi network/secretory vesicles, resulting in the production of mature somatostatin peptides. To test this hypothesis, we investigated the processing pattern of two different hybrid precursors: the 52-1 hybrid precursor, which has a Glu-Ala spacer between the prepro region of alpha-factor and somatostatin, and the 58-1 hybrid precursor, which lacks the Glu-Ala spacer. Processing of metabolically labeled hybrid propeptides to smaller somatostatin peptides was assessed by HPLC. When pulse-labeled cells were chased for up to 2 h, 68% of the initially synthesized propeptides were secreted constitutively. About 22% of somatostatin-related products were proteolytically processed to mature somatostatin, of which 38.7% were detected intracellularly after 2 h. From N-terminal peptide sequence determination of somatostatin-related products in GH(3)-52 and GH(3)-58 cells, we found that both hybrid precursors were accurately cleaved at their dibasic amino acid sites. Notably, we also observed that the Glu-Ala spacer sequence was removed from 52-1 hybrid precursors. The latter result strongly suggests that a novel dipeptidyl aminopeptidase activity - a yeast STE13-like enzyme - is present in the post-trans Golgi network compartment of GH(3) cells. The data from these studies indicate that mechanisms which control protein secretion are conserved between yeast and mammalian cells.
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PMID:Evidence of a novel dipeptidyl aminopeptidase in mammalian GH(3) cells: new insights into the processing of peptide hormone precursors. 1220 45

A somatostatin deficit occurs in the cerebral cortex of Alzheimer's disease patients without a major loss in somatostatin-containing neurons. This deficit could be related to a reduction in the rate of proteolytic processing of peptide precursors. Since the two proprotein convertases (PC)1 and PC2 are responsible for the processing of neuropeptide precursors directed to the regulated secretory pathway, we examined whether they are involved first in the proteolytic processing of prosomatostatin in mouse and human brain and secondly in somatostatin defect associated with Alzheimer's disease. By size exclusion chromatography, the cleavage of prosomatostatin to somatostatin-14 is almost totally abolished in the cortex of PC2 null mice, while the proportions of prosomatostatin and somatostatin-28 are increased. By immunohistochemistry, PC1 and PC2 were localized in many neuronal elements in human frontal and temporal cortex. The convertases levels were quantified by Western blot, as well as the protein 7B2 which is required for the production of active PC2. No significant change in PC1 levels was observed in Alzheimer's disease. In contrast, a marked decrease in the ratio of the PC2 precursor to the total enzymatic pool was observed in the frontal cortex of Alzheimer patients. This decrease coincides with an increase in the binding protein 7B2. However, the content and enzymatic activity of the PC2 mature form were similar in Alzheimer patients and controls. Therefore, the cortical somatostatin defect is not due to convertase alteration occuring during Alzheimer's disease. Further studies will be needed to assess the mechanisms involved in somatostatin deficiency in Alzheimer's disease.
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PMID:The proprotein convertase PC2 is involved in the maturation of prosomatostatin to somatostatin-14 but not in the somatostatin deficit in Alzheimer's disease. 1461 8

Although cortistatin (CST) shares great structural homology with somatostatin (SST) and binds to all SST receptor subtypes with similar affinity, these neurohormones have divergent biological roles, as evidenced by their different patterns of tissue expression and biological actions. Moreover, CST, but not SST, can bind to the proadrenomedullin N-terminal peptide (PAMP) receptor MrgX2 and type 1a growth hormone secretagogue (GHS) receptor (GHSR-1a), also known as the 'ghrelin' receptor. These findings suggest that CST-specific actions could be mediated by the GHSR-1a and CST might represent a link between the ghrelin and the SST systems. Here, we review the data leading to this working hypothesis and discuss the in vitro, in vivo and clinical implications of potential SST-receptor-independent, GHSR-1a-mediated neuroendocrine and metabolic effects of CST.
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PMID:Brain-gut communication: cortistatin, somatostatin and ghrelin. 1763 10

Prohormone convertases (PCs) are proteinases that cleave inactive prohormones to biologically active peptides. Seven PCs have been identified; two of them, PC1/3 and PC2, have only been localized in neuroendocrine (NE) tissues; a third, furin, in both endocrine and exocrine tissues. We have studied the immunoreactivity of PC1/3, PC2 and furin in the four major NE cell types of the human pancreas by using double immunofluorescence techniques. The study also included the expression of NE secretory protein 7B2 (secretogranin V), a member of the granin family, which influences the function of PC2. The results showed that the three PCs and 7B2 were expressed only in endocrine pancreas, furin also in exocrine cells. Insulin (B) cells harboured PC1/3 and PC2, but not furin. Glucagon (A) cells were immunoreactive to all three PCs; all glucagon cells expressed PC2, but one subpopulation showed PC1/3 immunoreactivity and another furin. Only a few somatostatin (D) cells contained PC2, but no other proconvertase. Pancreatic polypeptide (PP) cells were non-reactive to all three PCs. 7B2 occurred only in insulin and glucagon cells. A varying co-localization pattern was observed between PCs and between PCs and 7B2, with the exception of PC1/3 and furin which were not co-localized. In conclusion, our study shows that PCs are localized in insulin and glucagon cells and do seem to be important in these cell types for processing of hormone and other protein precursors, especially chromogranins, but for the two other major cell types probably other enzymes are of importance.
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PMID:Prohormone convertases 1/3, 2, furin and protein 7B2 (Secretogranin V) in endocrine cells of the human pancreas. 1795 63

Carcinoids of the intestine are the most common gastrointestinal carcinoid tumors. Therapeutic options to treat patients with these tumors are limited. There are very few ileal carcinoid cell lines available for in vitro studies to analyze new drugs that could be effective in treating patients with metastatic tumors. A replication defective recombinant adenovirus with an SV40 early T-antigen insert was used to infect two intestinal carcinoid tumors to create carcinoid cell lines. The cell lines were studied by cell culture, reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry. Both cell lines expressed SV40 large T antigen and receptors for TGFbeta1, TGFbeta2, EGFR, and somatostatin receptors. Treatment with TGFbeta1 led to growth inhibition and increased apoptosis in the cultured cells. Octreotide inhibited cell growth of both cell lines while stimulating apoptosis. Treatment of the HC45 cells with gefitinib also inhibited cell growth in a concentration-dependent manner. TGFbeta treatment stimulated chromogranin A expression while expression of two other granins, chromogranin B and 7B2, did not change significantly. RNA profiling of cells treated with TGFbeta1 showed increased expression of vitamin D3 receptor. This finding was validated by real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. These results indicate that these carcinoid cell lines can be used to study the proliferative and apoptotic mechanisms involved in intestinal carcinoid tumor growth regulation.
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PMID:Characterization of the functional and growth properties of cell lines established from ileal and rectal carcinoid tumors. 1824 65

Cortistatin (CST) shares high structural homology with somatostatin (SST) and binds all SST-receptors (SST-R) subtypes with similar affinity. However, CST actions, tissue expression patterns and regulation do not fully overlap with those of SST, and, moreover, CST, but not SST, also binds and activates proadrenomedullin N-terminal peptide receptor (MrgX2) and shows binding affinity to ghrelin receptor (GHS-R1a). Several studies performed to clarify the endocrine actions of CST, compared with SST, showed that, in humans, CST and SST share the same endocrine actions, i.e. inhibition of GH and insulin secretion in physiological conditions and in acromegaly. A similar inhibitory effect on PRL and ACTH secretion was shown in acromegaly, prolactinoma or in Cushing's disease. This identity of endocrine actions by CST and SST suggests that SST-R activation by CST overrides any other independent action of this peptide mediated by other receptors. Thus, in terms of endocrine actions, CST can well be considered a natural alternative to SST.
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PMID:Endocrine actions of cortistatin: in vivo studies. 1828 Nov 48

Pax6 is important in the development of the pancreas and was previously shown to regulate pancreatic endocrine differentiation, as well as the insulin, glucagon, and somatostatin genes. Prohormone convertase 2 (PC2) is the main processing enzyme in pancreatic alpha cells, where it processes proglucagon to produce glucagon under the spatial and temporal control of 7B2, which functions as a molecular chaperone. To investigate the role of Pax6 in glucagon biosynthesis, we studied potential target genes in InR1G9 alpha cells transfected with Pax6 small interfering RNA and in InR1G9 clones expressing a dominant-negative form of Pax6. We now report that Pax6 controls the expression of the PC2 and 7B2 genes. By binding and transactivation studies, we found that Pax6 indirectly regulates PC2 gene transcription through cMaf and Beta2/NeuroD1 while it activates the 7B2 gene both directly and indirectly through the same transcription factors, cMaf and Beta2/NeuroD1. We conclude that Pax6 is critical for glucagon biosynthesis and processing by directly and indirectly activating the glucagon gene through cMaf and Beta2/NeuroD1, as well as the PC2 and 7B2 genes.
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PMID:Pax6 regulates the proglucagon processing enzyme PC2 and its chaperone 7B2. 1922 71


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