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)

Cortistatin (CST) is a recently discovered neuropeptide from the somatostatin gene family named after its predominantly cortical expression and ability to depress cortical activity. CST shows many remarkable structural and functional similarities to its related neuropeptide somatostatin. However, the many physiological differences between CST and somatostatin are just as remarkable as the similarities. CST-14 shares 11 of its 14 amino acids with somatostatin-14, including the FWKT tetramer thought to be responsible for somatostatin's receptor interactions and the pair of cysteine residues that likely render the peptides cyclic. Yet the nucleotide sequences and chromosomal localizations of these genes clearly indicate they are products of separate genes and CST's activity in the brain is widely distinct from that of somatostatin. Now cloned from human, mouse and rat sources, in vitro assays show that CST is able to bind all five cloned somatostatin receptors and shares many pharmacological and functional properties with somatostatin, including the depression of neuronal activity and inhibition of GH release. However, distinct from somatostatin, CST has been shown to induce slow-wave sleep, reduce locomotor activity, and activate cation selective currents not responsive to, or antagonized by, somatostatin. Here we address the discovery and characterization of this novel somatostatin-like neuropeptide, including its cloning, expression and pharmacology. We also examine the evidence pointing towards a specific receptor for this novel neuropeptide member of the somatostatin gene family.
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PMID:Cortistatin: a natural somatostatin analog. 1662 39

Among hormones and neuropeptides influencing the immune system, somatostatin seems to play a key role not only in inhibiting specific immune cell activities, but also in promoting selected functions of particular immune cell subsets. Indeed, controversial effects have been observed in experimental conditions where somatostatin seems to stimulate certain cell functions, such as secretion of specific products (immunoglobulin, cytokines), cell migration and adhesion to extracellular matrix components. However, interestingly, cortistatin (CST), a neuropeptide that strongly resembles somatostatin, from both the structural and functional points of view, seems to have potential roles in regulating immune responses, as well as other lymphoid cell functions. The unexpected wide distribution of CST in a number of human organs, but particularly in immune cells, points to a broader physiological role of CST than previously presumed. The actions of somatostatin and its synthetic analogs (SSA) are mediated by five membrane G protein-coupled receptors subtypes (SSTR1-5), displaying a tissue specific distribution. The majority of somatostatin-target tissues, including lymphoid tissues, may co-express multiple somatostatin receptor (SSTR). The number of SSTRs in lymphoid cells is significantly lower compared to neuroendocrine tissues. However, the presence of receptors allowed the localization by in vivo SSTR scintigraphy of lymphoproliferative disorders, as well as granulomatous and autoimmune diseases. In specific cases, this technique may contribute to establishing the diagnosis and staging the disease. Recent studies evaluating the specific and quantitative SSTR distribution in lymphoid organs and cells, in both normal conditions and immune disorders, have largely contributed to better understand the phenomenology of in vivo receptor imaging and also the involvement of the different SSTR in determining the uptake of radiolabeled SSAs. Moreover, since lymphomas are highly radiosensitive malignancies, a promising approach in refractory patients with malignant lymphomas may be represented by radionuclide-targeted therapy with radioactive-coupled SSAs combined with gene therapy. This latter technique seems effective in inducing the expression or increasing the number of given SSTR in order to ameliorate the impact of radionuclide-targeted therapy. Medical treatment of lymphoproliferative diseases with currently available synthetic analogs have produced unsatisfactory and conflicting results. This might be due to the affinity of the current available SSAs for specific SSTR. However, the synthesis of new compounds with distinct properties has reopened a challenge in this field. The application of receptor-based localization and anti-tumor strategies should also be taking into account the new knowledge recently emerged on the physiopathology of neuropeptide receptors: firstly, neuropeptide receptor homo- and heterodimerization, which may involve different subtypes of SSTRs, as well as other neuropetide receptors, and secondly, the role of endogenous SSTR ligands, such as CST.
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PMID:Potential indications for somatostatin analogues: immune system and limphoproliferative disorders. 1662 59

At first sight, the title is confusing as it seems to try to merge four unrelated topics into a single presentation. Somatostatin, cortistatin (CST) and ghrelin display broad biological activities, including metabolic effects. However, although apparently unrelated, these peptides entities have more in common than it might be expected and their reciprocal interactions give a new perspective to the hormonal regulation of glucose metabolism. Let's analyze the ghrelin receptor subtype GH secretagogue (GHS)-receptor 1a (R1a). Taking into account the GHS-R1a as receptor of reference, acylated ghrelin is one of its natural ligands. Interestingly, it has been demonstrated that also CST, a neuropeptide, binds with high affinity to the GHS-R1a in human hypothalamus and pituitary tissues. CST is a recently described neuropeptide showing high structural homology with somatostatin that binds to all somatostatin receptor subtypes (SSTRs) with an affinity (1-2 nM). In fact, CST and somatostatin exhibit the same endocrine activities. The existence of specific receptors which selectively bind somatostatin or CST has been hypothesized, based on evidence that CST possesses an action profile different from somatostatin and that CST and somatostatin are often co-expressed in the same neurons but are regulated by different stimuli. Given these findings, the ability of CST to bind the GHS-R1a is of particular relevance because somatostatin and its fragments do not bind the same receptor. Interestingly, the classical synthetic somatostatin analogs, i.e. octreotide, lanreotide and vapreotide bind the GHS-R1a with an affinity lower than that of CST. These findings have generated the hypothesis that CST, because of its ability to bind both SSTRs and GHSRs, would represent the link between ghrelin and "somatostatin/CST" system that had not previously been demonstrated. On the other hand, the GHS-R1a is unlikely to be the only GHS-R. It has been already demonstrated that a GHS-R subtype able to bind non-acylated as well as acylated ghrelin exists and likely mediates biological activities. Another GHS-R subtype likely mediates the influence of unacylated ghrelin on glucose metabolism, since it does not bind nor activates the GHS-R1a. Given this complexity, it is clear that further studies are required to clarify whether ghrelin is the sole ligand or one of a number of ligands activating the GHS-R 1a and whether that receptor used for ghrelin isolation is the sole receptor or one of a group of receptors for such ligands.
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PMID:Somatostatin, cortistatin, ghrelin and glucose metabolism. 1662 61

Somatostatin-14 (SRIF) co-localizes with gamma-aminobutyric acid (GABA) in the hippocampus and regulates neuronal excitability. A role of SRIF in the control of seizures has been proposed, although its exact contribution requires some clarification. In particular, SRIF knockout (KO) mice do not exhibit spontaneous seizures, indicating that compensatory changes may occur in KO. In the KO hippocampus, we examined whether specific SRIF receptors and/or the cognate peptide cortistatin-14 (CST) compensate for the absence of SRIF. We found increased levels of both sst2 receptors (sst2) and CST, and we explored the functional consequences of sst2 compensation on bursting activity and synaptic responses in hippocampal slices. Bursting was decreased by SRIF in wild-type (WT) mice, but it was not affected by either CST or sst2 agonist and antagonist. sst4 agonist increased bursting frequency in either WT or KO. In WT, but not in KO, its effects were blocked by agonizing or antagonizing sst2, suggesting that sst2 and sst4 are functionally coupled in the WT hippocampus. Bursting was reduced in KO as compared with WT and was increased upon application of sst2 antagonist, while SRIF, CST and sst2 agonist had no effect. At the synaptic level, we observed that in WT, SRIF decreased excitatory postsynaptic potentials which were, in contrast, increased by sst2 antagonist in KO. We conclude that sst2 compensates for SRIF absence and that its upregulation is responsible for reduced bursting and decreased excitatory transmission in KO mice. We suggest that a critical density of sst2 is needed to control hippocampal activity.
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PMID:Compensatory changes in the hippocampus of somatostatin knockout mice: upregulation of somatostatin receptor 2 and its function in the control of bursting activity and synaptic transmission. 1670 48

Cortistatin is a recently discovered neuropeptide that is structurally related to somatostatin, the classic inhibitor of growth hormone (GH) release. Cortistatin binds with high affinity to all five somatostatin receptors (sst1-5), and, like somatostatin, cortistatin inhibits in vivo GH release in man and rats. In this report, we compared the in vitro actions of cortistatin and somatostatin using primary pig pituitary cell cultures. In this species, we have previously reported that somatostatin not only inhibits GH-releasing hormone (GHRH)-stimulated GH release at high doses, but also stimulates basal GH release at low (pM) doses, a dual response that is markedly dependent on the subpopulation of pituitary somatotropes examined. Results reported herein demonstrate that cortistatin closely mimics the dose-dependent inhibitory and stimulatory effects of somatostatin on GH secretion. As cortistatin, unlike somatostatin, binds to the human receptor for ghrelin/GH secretagogs (GHS-R), we also investigated whether cortistatin stimulates GH release through this receptor by using a synthetic, short form of cortistatin, cortistatin-8 (CST8), which lacks the sst-binding capacity of full-length cortistatin but retains its GHS-R-binding capacity. Interestingly, CST8 stimulated GH release only at low doses (10(-15) M), and did not reduce GH secretion stimulated by GHRH, ghrelin, or low-dose, full-length cortistatin, yet it counteracted that induced by a nonpeptidyl GHS, L-163 255. Taken together, our results indicate that the dual, inhibitory and stimulatory effects of cortistatin on GH release closely parallel those of somatostatin and are probably mediated by the same receptor(s) and signaling pathway(s) for both peptides. Furthermore, they suggest that the pathway(s) activated by cortistatin (and somatostatin) to stimulate GH release are not initiated by GHS-R activation.
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PMID:Cortistatin mimics somatostatin by inducing a dual, dose-dependent stimulatory and inhibitory effect on growth hormone secretion in somatotropes. 1672 Jul 22

Hormones and neuropeptides may influence the activities of lymphoid organs and cells via endocrine and local autocrine/paracrine pathways. A paradigm of the interactions between the neuroendocrine and immune system is sophisticatedly represented in the thymus. Indeed, receptors for these molecules are heterogeneously expressed in all subsets of thymic cells, and the communications are tuned by feedback circuitries. Herein, we focus on somatostatin (SS), a ubiquitous peptide that regulates several physiological cell processes and acts via five specific receptor (SSR) subtypes (sst(1-5)). Neuronal and accessory cells, so-called neuroendocrine cells, and immune cells, heterogeneously express SSRs. The functional characterization of SSRs in vivo by nuclear medicine techniques opened a complex scenario on the significance of SS/SSR pathway in immune system and related diseases. Several studies have established that SSR scintigraphy may benefit patients with chronic inflammatory and granulomatous diseases, as well as lymphoproliferative diseases. The results are sufficiently promising to warrant larger studies aimed at defining the exact role of these techniques. The development of SS analogs with antisecretory and antiproliferative effects has radically changed the management of neuroendocrine tumors. Moreover, very important recent findings, emerging from in vitro studies on SSR physiology in immune cells, will certainly expand the potential applications of SS analogs for in vivo diagnostic and therapeutic options. Indeed, the anti-inflammatory and analgesic effects of these drugs remain incompletely understood, but may prove useful in a number of autoimmune diseases. Because SS expression is absent in different immune tissues where SSRs are present, the existence of another ligand was hypothesized. In fact, it has been recently demonstrated that human lymphoid tissues and immune cells may express cortistatin (CST). CST is known to bind SSRs and shares many pharmacological and functional properties with SS. However, CST has also properties distinct from SS, and the higher expression of CST in immune cells supports the hypothesis that CST rather than SS may act as a potential endogenous ligand for SSRs in the human immune system.
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PMID:Neuroendocrine-immune interactions: the role of cortistatin/somatostatin system. 1685 40

The recent development of a specific radioimmunoassay for amphibian (bullfrog, Rana catesbeiana) thyrotropin (TSH) has made it possible to study the effects of various neuropeptides on the release of TSH from the pituitary in vitro. Up to now, corticotropin-releasing factor of bullfrog origin has been shown to have a potent TSH-releasing activity, whereas gonadotropin-releasing hormone and TSH-releasing hormone exhibit a moderate TSH-releasing effect on the adult, but not larval, pituitary. In the present study, the effects of pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), and somatostatin (SS) on the in vitro release of TSH from the bullfrog pituitary were investigated. Both frog (R. ridibunda) PACAP-38 and PACAP-27 caused a concentration-dependent stimulation of the release of TSH from dispersed pituitary cells during a 24-h culture. The PACAP-38- and PACAP-27-induced TSH release was suppressed by a simultaneous application of PACAP6-38. Application of high concentrations of PACAP6-38 alone caused a slight but significant stimulatory effect on the release of TSH. Frog VIP also stimulated TSH release from pituitary cells concentration-dependently. Frog SS1 (homologous to mammalian somatostatin-14) and SS2 (homologous to mammalian cortistatin) did not affect the basal release of TSH but caused a concentration-dependent suppression of the PACAP-38-induced release of TSH. These results suggest the involvement of multiple neuropeptides in the regulation of the release of TSH from the amphibian pituitary.
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PMID:Effects of pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide, and somatostatin on the release of thyrotropin from the bullfrog pituitary. 1688 12

The induction of immune tolerance is critical for the prevention of autoimmunity and the maintenance of immune homeostasis. The identification of factors involved in the maintenance or restoration of such tolerance has become the focus of new therapies for inflammatory and autoimmune diseases. Cortistatin, a recently discovered cyclic neuropeptide related to somatostatin, has emerged as a potential endogenous antiinflammatory factor based on its production by, as well as its binding to, immune cells. Thus, cortistatin has been found to downregulate the inflammatory response mediated by activated macrophages. The present work reviews various recent studies involving different experimental models of sepsis, rheumatoid arthritis and inflammatory bowel disease, demonstrating that cortistatin treatment offers great benefits at both the clinical and pathological levels. These include the downregulation of both inflammatory and Th1-mediated autoimmune disease components and the emergence of regulatory T cells (Treg) that suppress autoreactive T cells, both of which contribute to the restoration of immune tolerance. While many questions need to be resolved, cortistatin appears to be an exciting and promising candidate for the treatment of several chronic inflammatory diseases and autoimmune disorders.
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PMID:Cortistatin as a potential multistep therapeutic agent for inflammatory disorders. 1708 Feb 2

Somatostatin (SRIF)-14 is recognized as an important mediator between the nervous and the immune system, although the functional role of its receptors (sst(1)-sst(5)) is poorly understood in humans. In our study, we demonstrate that human macrophages, differentiated from PBMC-derived monocytes, express sst(1) and sst(2) mRNAs. sst(1) and sst(2) are mostly localized at the cell surface and display active binding sites. In particular, sst(1)/sst(2) activation results in a weak internalization of sst(1), and the sst(2) internalization appears more efficient. At the functional level, the activation of SRIF receptors by the multiligand analogs SOM230 and KE108, but not by SRIF-14 or cortistatin-14, reduces macrophage viability. Their effects are mimicked by the selective activation of sst(1) and sst(2) using CH-275 and SMS 201-995/L-779,976, respectively. Further, sst(1)- and sst(2)-mediated effects are reversed by the sst(1) antagonist SRA-880 or the sst(2) antagonist CYN 154806, respectively. CH-275, SMS 201-995, and L-779,976, but not SRIF-14, decrease mRNA expression and secretion of the MCP-1. In addition, SRIF-14, CH-275, SMS 201-995, and L-779,976 decrease IL-8 secretion, and they do not affect IL-8 mRNA expression. In contrast, SRIF-14 and sst(1)/sst(2) agonists do not affect the secretion of matrix metalloproteinase-9. Collectively, our results suggest that the SRIF system, through sst(1) and sst(2), exerts mainly an immunosuppressive effect in human macrophages and may, therefore, represent a therapeutic window that can be exploited for the development of new strategies in pharmacological therapy of inflammation.
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PMID:Expression, pharmacology, and functional role of somatostatin receptor subtypes 1 and 2 in human macrophages. 1714 91

Cortistatin (CST) is a recently discovered neuropeptide from the somatostatin gene family, named after its predominantly cortical expression and ability to depress cortical activity. CST shows many remarkable structural and functional similarities to its related neuropeptide somatostatin, or somatotropin release-inhibiting factor. However, the many physiological differences between CST and somatostatin are just as remarkable as the similarities. CST-29 has recently been shown to prevent inflammation in rodent models for human diseases, raising novel therapeutic properties to this neuropeptide. In this review, the authors address a new possible role for CST in the immune system and evaluate the possible therapeutic use of CST to treat disorders associated with inflammation.
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PMID:Cortistatin as a therapeutic target in inflammation. 1715 30


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