Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cortistatin (CST), a 17-amino acid peptide partially homologous to somatostatin (SRIF), has been originally isolated from the cerebral cortex and recently found in monocytes and macrophages of the immune system. CST binds all 5 SRIF receptors, as well the GH secretagogue (GHS)/ghrelin receptors. CST exerts sleep promoting activities, acts on animal motility and behavior and inhibits GH and insulin secretion. To investigate the possible occurrence and activities in peripheral tissues, expression of CST at the mRNA and peptide level was analyzed in the human pancreas by means of RT-PCR, in situ hybridization and immunohistochemistry. The specific CST mRNA was found in 3 of 4 pancreatic RNA extracts and in the control cerebral cortex. By in situ hybridization, CST mRNA was localized in the pancreatic islets, but not in the exocrine pancreas. This finding was confirmed by immunostaining with a specific antibody to CST-17 which detected CST in single islet cells. These cells also expressed SRIF receptors types 2, 3 and 5, ghrelin and GHS receptors. Thus, our findings show the presence of CST in the human endocrine pancreas. Local autocrine or paracrine circuits, only in part overlapped with those of SRIF, may be active to modulate insulin and/or glucagon levels.
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PMID:Presence of cortistatin in the human pancreas. 1466 20

Cortistatin is a neuropeptide structurally related to somatostatin that induces sleep and interferes with the memory process. Very likely affecting other neurotransmission systems, such as: acetylcholine, gamma-aminobutyric acid, and noradrenaline. For example, cortistatin inhibits acetylcholine excitatory actions in the hippocampus. It is known that acetylcholine is involved in the regulation of several processes, such as pain, temperature, sleep, and memory. Since cortistatin seems to interact with acetylcholine, we decided to explore whether cortistatin participates in the system that modulates the noxious stimulus-evoked behavior. The intracerebroventricular administration of cortistatin increased the threshold to evoke a defensive behavior by a nociceptive stimulus. These observations suggest that cortistatin is part of the system that regulates pain perception.
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PMID:Cortistatin, a modulatory peptide of sleep and memory, induces analgesia in rats. 1470 Jul 41

Somatostatin and cortistatin, a recently discovered endogenous neuropeptide relative of somatostatin, have multiple modulatory effects on the immune system. The specific somatostatin receptor distribution might in part explain the heterogeneity of effects of somatostatin or its analogs on immunocytes. In fact, somatostatin receptor subtypes are differentially expressed on specific cell subsets within the organs of the immune system and the expression is dynamically regulated and seems to depend on the traffic of these cells through and within lymphoid structure and homing in tissues. Somatostatin effects on immune cells are mainly based on autocrine and paracrine modes of action. In fact, activated cells producing somatostatin (or cortistatin) may interact with other cells expressing the receptors. Here, we review the postulated modes of action of somatostatin and somatostatin-like peptides, including the currently available synthetic somatostatin analogs, in cells of the immune system. We also discuss the wide distribution of somatostatin and its specific five receptor subtypes in immune cell lines, as well as throughout animal and human lymphoid organs, in both normal and pathological conditions.
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PMID:Somatostatin receptor distribution and function in immune system. 1507 14

Cortistatin (CST) is a neuropeptide, which binds with high affinity all somatostatin (SS) receptor subtypes and shows high structural homology with SS itself. A receptor specific for CST only, i.e., not recognized by SS, has been recently described in agreement with data reporting that not all CST actions are shared by SS. Interestingly, CST but not SS also binds ghrelin receptor (GHS-R1a) in vitro, suggesting a potential interplay between CST and ghrelin system. The aim of this study was to investigate in humans the endocrine and metabolic activities of human CST-17 in comparison with rat CST-14 that has previously been shown to exert the same endocrine actions of SS in healthy volunteers. To this aim, in six healthy male volunteers (age [median, 3rd-97th centiles]: 28.5; 23.6-34.3 years; Body Mass Index: 23.5; 21.0-25.1 kg/m(2)), we studied the effects of human CST-17 (2.0 microg/kg/h iv over 120 min), rat CST-14 (2.0 microg/kg/h iv over 120 min) and SS-14 (2.0 microg/kg/h iv over 120 min) on: (a) spontaneous GH, ACTH, PRL, cortisol, insulin and glucose levels; (b) the GH responses to GHRH (1.0 microg/kg iv at 0 min); (c) the GH, PRL, ACTH, cortisol, insulin and glucose responses to ghrelin (1.0 microg/kg iv at 0 min). CST-17 inhibited (p < 0.01) basal GH secretion to the same extent of CST-14 and SS-14. Spontaneous PRL, ACTH and cortisol secretion were not significantly modified by CST-17, CST-14 or SS-14. CST-17 as well as CST-14 and SS-14 also inhibited (p < 0.05) spontaneous insulin secretion to a similar extent. None of these peptides modified glucose levels. The GH response to GHRH was inhibited to the same extent by CST-17 (p < 0.01), CST-14 (p < 0.01) and SS-14 (p < 0.05 ). The ghrelin-induced GH response was higher than that elicited by GHRH (p < 0.01) and inhibited by CST-17 (p < 0.05) as well as by CST-14 (p < 0.05) and SS-14 (p < 0.01). The PRL, ACTH and cortisol responses to ghrelin were unaffected by CST-17, CST-14 or SS-14. On the other hand, the inhibitory effect of ghrelin on insulin levels was abolished by CST-17, CST-14 or SS-14 (p < 0.05) that, in turn, did not modify the ghrelin-induced increase in glucose levels. In conclusion, this study demonstrates that human CST-17 and rat CST-14 exert the same endocrine activities of SS in humans. The endocrine actions of human and rat CST therefore are likely to reflect activation of classical SS receptors.
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PMID:Cortistatin-17 and -14 exert the same endocrine activities as somatostatin in humans. 1533 31

Cortistatin-14 (CST-14) is a recently discovered member of the somatostatin family of neuropeptides. It shares 11 of its 14 amino acids with somatostatin-14 (SRIF-14). In the present study, binding sites for cortistatin-14 in the mouse brain were examined and compared to those for somatostatin using iodinated cortistatin-14 and iodinated somatostatin-14. By in vitro receptor autoradiography, high densities of cortistatin-14 and somatostatin-14 specific binding sites were detected in the cortex, hippocampal formation, basolateral amygdala and medial habenula. Unlabeled 100 nM cortistatin-14 inhibited iodinated somatostatin-14 binding in the hippocampus, but not in the cortex or amygdaloid nuclei. In somatostatin receptor subtype-2 knock-out (KO) mice, autoradiographic iodinated somatostatin-14 binding was observed in the hippocampus and habenula but was removed in the cortex and amygdaloid nuclei, specific iodinated cortistatin-14 binding sites were found in the hippocampus, habenula and throughout the cortex. We conclude that the somatostatin receptor subtype-2 is responsible for somatostatin binding in cortical and amygdaloid regions and that cortistatin predominantly interacts with the same receptors as somatostatin.
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PMID:Cortistatin radioligand binding in wild-type and somatostatin receptor-deficient mouse brain. 1554 57

There is now evidence for the existence of two somatostatin genes in most vertebrate species, and even three somatostatin genes in teleosts. To help clarify the evolutionary relationships between the different somatostatin isoforms currently known, we characterized the somatostatin loci in a teleost species, the zebrafish Danio rerio, and compared them with the corresponding regions in the human and pufferfish genomes. The occurrence of three somatostatin genes, termed SS1, SS2 and SSII, has been previously demonstrated in the zebrafish. Radiation hybrid mapping assigned these three genes to linkage groups 15, 23 and 2, respectively. Conserved synteny of the zebrafish SS2 gene and the human cortistatin gene was revealed by comparative genomic analysis, indicating that mammalian cortistatin is orthologous to the SS2 variant of non-mammalian species. In contrast, using a similar approach, it was not possible to identify the evolutionary relationships between the atypical SSII gene of zebrafish and the other teleost SSII genes.
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PMID:Chromosomal localization of three somatostatin genes in zebrafish. Evidence that the [Pro2]-somatostatin-14 isoform and cortistatin are encoded by orthologous genes. 1559 Oct 18

Somatostatin receptor 2 (SSTR2) mediates neuromodulatory signals of somatostatin and cortistatin in the cerebral cortex. Recently, SSTR2 has been shown to enhance conserved death ligand- and mitochondria-mediated apoptotic pathways in non-neuronal cells. Whether somatostatin receptors are activated in cerebrocortical neurons and contribute to neurodegeneration after experimental focal ischemia was unknown until now. Here we examined internalization of SSTR2 in a rat model of middle cerebral artery occlusion (MCAO) by confocal microscopy. At 3 and 6 hr after MCAO, SSTR2 was internalized excessively in cerebrocortical neurons adjacent to the infarct, which was prevented by intracerebroventricular application of the SSTR2-selective antagonist BIM-23627. SSTR2 internalization was associated with a transient depletion of somatostatin from axonal terminals and increased expression of SSTR2 mRNA. The initial loss of somatostatin was followed by an increase in somatostatin mRNA levels, whereas cortistatin mRNA expression was decreased. In SSTR2-deficient mice with lacZ under the control of the SSTR2 promoter, MCAO-induced upregulation of SSTR2 gene expression was less pronounced than in wild types. SSTR2-deficient mice exhibited a 40% reduction of infarct size after permanent distal MCAO and a 63% reduction after transient proximal MCAO. In summary, we provide direct evidence for activation of SSTR2 by an endogenous ligand after focal ischemia. Activation of functional SSTR2 receptors contributes to increased SSTR2 gene expression and postischemic neurodegeneration.
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PMID:Somatostatin receptor 2 is activated in cortical neurons and contributes to neurodegeneration after focal ischemia. 1560 46

Several neuropeptides affect the sleep-wake cycle, for example, vasoactive intestinal polypeptide, cholecystokinin octapeptide, orexin, somatostatin, insulin, leptin, ghrelin, neuropeptide Y and cortistatin, which regulate food ingestion. There are also proteins from the immunological system: tumor necrosis factor-alpha, interleukin (IL)-1beta IL-4, IL-10, IL-13, as well as trophic molecules, such as growth hormone-releasing hormone, growth hormone, prolactin, brain-derived neurotrophic factor and nerve growth factor, neurotrophin-3 and neurotrophin-4. Based on this information, we believe that some functions of sleep can be suggested. One of these functions could be the regulation of energy, since many, if not all, of the neuropeptides that regulate feeding affect the level of alertness. Likewise, the immunological system and the trophic molecules establish a dialog with the brain during sleep in order to reestablish neuronal structure. These proteins are the expression of genes that accomplish the function of regulating our waking and our sleep, suggesting the important control the genome is exerting on this activity.
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PMID:The role of neuropeptides in sleep modulation. 1560 11

This study investigated the neuroprotective effect of somatostatin, cortistatin and agonists at somatostatin(2) (sst(2)) receptors in retinal explants subjected to chemical ischaemia. Eyecups of female Sprague-Dawley rats (250-300 g) were immersed in PBS buffer or PBS containing iodoacetic acid (IAA; 0.5, 5, 50, 100 mM) and sodium cyanide (NaCN; 2.5, 25, 250, 500 mM) (chemical ischaemia solution) for 15, 30, 45, 60, 120 min (pilot study). Subsequently, eyecups were incubated with (1) PBS, (2) chemical ischaemia solution (5 mM IAA/25 mM NaCN) or (3) somatostatin, cortistatin, BIM23014 or MK678 (0.1, 1, 10 microM) together with the chemical ischaemia solution for 60 min, followed by a second 60-min incubation in PBS (control and ischaemia groups) or ligands in PBS (neuroprotection groups). The eyecups were subsequently fixed and sectioned for immunohistochemistry. Treatment of the eyecups with IAA/NaCN (5/25 mM) for 60 min abolished choline acetyltransferase (ChAT), tyrosine hydroxylase and brain nitric oxide synthase immunoreactivity in the inner nuclear, inner plexiform and ganglion cell layers. It also abolished protein kinase C immunoreactivity in rod bipolar cells and terminals, but did not damage ganglion cells labelled for microtubule-associated protein-1. TUNEL staining provided evidence of cell death in the ischaemic retina. Cortistatin, BIM23014 and MK678 attenuated the retinal damage caused by the chemical ischaemia in a concentration dependent manner. The ligands afforded approximately 58, 76 and 49% neuroprotection, respectively, of the ChAT immunoreactive cells. These results demonstrate that somatostatin analogues can protect the retina from ischaemic damage. The chemical ischaemia model is presently employed for the elucidation of the mechanisms involved in the neuroprotection.
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PMID:Effect of somatostatin analogues on chemically induced ischaemia in the rat retina. 1564 93

1 The fish somatostatin receptor 3 (fsst3) is one of the few somatostatin (SRIF) receptors cloned from a non-mammalian species so far. Here we extended our earlier characterization of this receptor by investigating the guanine nucleotide sensitivity of agonist radioligand binding at the fsst3 receptor recombinantly expressed in CCL39 (Chinese hamster lung fibroblast) cells. Further, we measured somatostatin (SRIF) and cortistatin (CST) analogues stimulated GTPgammaS binding, inhibition of forskolin-stimulated adenylate cyclase (FSAC) and stimulation of phospholipase C (PLC) activities. The present transductional data were then compared with previous radioligand binding and/or second messenger features determined for fsst3 and/or human SRIF receptors (hsst2, hsst3 and hsst5). 2 The GTP analogue guanylylimidodiphosphate (GppNHp) inhibited binding of [125I]CGP 23996 and [125I][Tyr3octreotide by 72 and 83% suggesting preferential labelling of G-protein-coupled fsst3 receptors. By contrast, [125I]LTT-SRIF28 and [125I][Tyr10]CST14 binding was rather GppNHp insensitive (42 and 35% inhibition) suggesting labelling of both coupled and non-coupled receptor states. These results might explain the apparent higher receptor densities determined in saturation experiments with [125I]LTT-SRIF28 and [125I][Tyr10]CST14 (4470 and 4030 fmol mg(-1)) compared with [125I]CGP 23996 and [125I][Tyr3]octreotide (3420 and 1520 fmol mg(-1)). 3 SRIF14 (10 microm)-stimulated specific [35S]GTPgammaS binding by three-fold; SRIF28 and octreotide displayed full agonism, whereas most other ligands displayed 60-80% intrinsic activity compared with SRIF14. SRIF14 and SRIF28 inhibited forskolin-stimulated AC (FSAC) activity by 60%; all tested ligands except BIM 23056 inhibited FSAC with comparable high intrinsic activities. SRIF14 stimulated PLC activity five- to six-fold, as determined by measuring total [3H] IP(x) accumulation; it was rather insensitive to pertussis toxin (PTX, 100 ng ml(-1), 21% inhibition), which suggests the G(q)-family proteins couple to PLC activity. SRIF14, SRIF28 and [Tyr10]CST14 showed full agonism at PLC, whereas all other ligands behaved as partial agonists (20-70% intrinsic activity). BIM 23056, which showed weak partial or no agonism, antagonized SRIF14-induced total [3H]-IP(x) production (pK(B) = 6.83), but failed to block competitively agonist-stimulated [35S]GTPgammaS binding or agonist-induced inhibition of FSAC activity. 4 Comparison of the pharmacological profiles of fsst3 receptors established in GTPgammaS binding, FSAC inhibition and PLC stimulation resulted in low correlations (r = 0.410-0.594). Both rank orders of potency and rank orders of relative efficacy varied in the three second messenger experiments. Significant, although variable correlations were obtained comparing GTPgammaS binding and inhibition of FSAC activity with previously reported affinity profiles of [125I]LTT-SRIF28, [125I][Tyr10]CST14, [125I]CGP 23996, [125I][Tyr3]octreotide (r = 0.75-0.83; 0.68-0.89). By contrast, the PLC stimulation and radioligand-binding profiles did not correlate. 5 Comparison of the functional data (GTPgammaS binding, FSAC inhibition, PLC stimulation) of fsst3 receptors with those of human sst2, sst3, sst5 receptors expressed in CCL39 cells resulted in highest correlation with the hsst5 receptor (r = 0.94, 0.97, 0.49) > hsst2 (0.80, 0.50, n.d.) > hsst3 (0.25, 0.19, 0.17). 6 In summary, fsst3 receptors expressed in CCL39 cells are involved in signalling cascades similar to those reported for mammalian SRIF receptors, suggesting SRIF receptors to be highly conserved in evolution. Binding and functional data showed highest similarity of fsst3 receptors with the human sst5 receptor subtype. Different affinities, receptor densities and GppNHp-sensitivities determined with the four radioligands (agonists) are assumed to results from ligand-specific states of the fsst3-ligand complex. The differences in the rank orders of potency and relative efficacy in the various signalling cascades may be explained by agonist-induced receptor trafficking.
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PMID:Fish somatostatin sst3 receptor: comparison of radioligand and GTPgammaS binding, adenylate cyclase and phospholipase C activities reveals different agonist-dependent pharmacological signatures. 1565 49


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