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) is a recently described neuropeptide. Although the expression of CST was initially reported to be restricted to the rat cerebral cortex and hippocampus, it is currently known to have wide distribution in many human organs. CST shares high homology with somatostatin and binds with high affinity to all somatostatin receptor (SSTR) subtypes. Indeed, many of its endocrine and biological activities overlap with somatostatin. However, CST and somatostatin are expressed in only partially overlapping cortical neuron populations. They are regulated by different stimuli, their cortical actions are diverse and CST, at variance with somatostatin, was shown to have a possible role in the human immune system. The activities specific to cortistatin may be attributable to its unique binding to the GH secretagogue (GHS) receptor (GHS-R) and the orphan G-protein-coupled receptor, MrgX2, which is not shared by somatostatin. The potential biological roles and therapeutic use of CST and the receptors involved in its action require further investigation.
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PMID:Cortistatin - a new neuroendocrine hormone? 1734 27

The present study investigated the presence of somatostatin receptor subtypes (ssts) and the endogenous peptides somatostatin and cortistatin in rat Kupffer cells, since modulation of these cells by somatostatin may be important for the beneficial effect of somatostatin analogues in a selected group of hepatocellular carcinoma patients. Kupffer cells were isolated from rat liver in agreement with national and EU guidelines. RT-PCR was employed to assess the expression of somatostatin, cortistatin and ssts in Kupffer cells. Western blot analysis and immunocytochemistry were employed to assess the expression and the localization of the receptors, respectively. Quiescent Kupffer cells were found to express sst(1-4) mRNA, while immunocytochemical studies supported the presence of only the sst(3) and sst(4) receptors, which were found to be internalized. However, sst1 and sst(2A) receptors were detected by western blotting. RT-PCR and RIA measurements support the presence of both somatostatin and cortistatin. Stimulation of the cells with LPS activated the expression of the sst(2), sst(3) and sst(4) receptors. The present data provide evidence to support the presence of ssts and the endogenous neuropeptides somatostatin and CST in rat Kupffer cells. Both peptides may act in an autocrine manner to regulate sst receptor distribution. Studies are in progress in order to further characterize the role of ssts in Kupffer cells and in hepatic therapeutics.
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PMID:RT-PCR and immunocytochemistry studies support the presence of somatostatin, cortistatin and somatostatin receptor subtypes in rat Kupffer cells. 1748 46

Neuropeptides are signaling molecules that interact with G-protein coupled receptors located both pre- and postsynaptically. Presynaptically, these receptors are localized in axons and terminals away from presynaptic specializations. Neuropeptides are stored in dense core vesicles that are distinct from the clear synaptic vesicles containing classic neurotransmitters such as glutamate and GABA. Because they require a stronger Ca(2+) signal than synaptic vesicles, dense core vesicles do not release neuropeptides with single action potentials but rather require high-frequency trains. Thus, neuropeptides only modulate strongly stimulated synapses, providing negative or positive feedback. Many neuropeptides have been found to inhibit glutamate release from presynaptic terminals, and the major mechanism is likely direct interaction of betagamma G-protein subunits with presynaptic proteins such as SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor). The use of mouse genetic models and specific receptor antagonists are beginning to unravel the function of inhibitory neuropeptides. The opioid receptors kappa and mu, which are activated by endogenous opioid peptides such as dynorphin, enkephalin, and possibly the endomorphins, are important in modulating pain transmission. Dynorphin, nociceptin/orphanin FQ, and somatostatin and its related peptide cortistatin appear to play a role in modulation of learning and memory. Neuropeptide Y has important functions in ingestive behavior and also in entraining circadian rhythms. The existence of neuropeptides greatly expands the computational ability of the brain by providing additional levels of modulation.
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PMID:Presynaptic inhibition of glutamate release by neuropeptides: use-dependent synaptic modification. 1755

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

It has been previously reported that male and female somatostatin (SST) knockout mice (Sst-/-) release more GH, compared with Sst+/+ mice, due to enhanced GH-secretory vesicle release. Endogenous SST may also regulate GH secretion by directly inhibiting GHRH-stimulated GH gene expression and/or by modulating hypothalamic GHRH input. To begin to explore these possibilities and to learn more about the gender-dependent role of SST in modulating GH-axis function, hypothalamic, pituitary, and liver components of the GH-axis were compared in male and female Sst+/+ and Sst-/- mice. Pituitary mRNA levels for GH and receptors for GHRH and ghrelin were increased in female Sst-/- mice, compared with Sst+/+ controls, and these changes were reflected by an increase in circulating GH and IGF-I. Elevated levels of IGF-I in female Sst-/- mice were associated with elevated hepatic mRNA levels for IGF-I, as well as for GH and prolactin receptors. Consistent with the role of GH/IGF-I in negative feedback regulation of hypothalamic function, GHRH mRNA levels were reduced in female Sst-/- mice, whereas cortistatin (CST) mRNA levels were unaltered. In contrast to the widespread impact of SST loss on GH-axis function in females, only circulating GH, hypothalamic CST, and hepatic prolactin receptor expression were up-regulated in Sst-/- male mice, compared with Sst+/+ controls. These results confirm and extend the sexually dimorphic role of SST on GH-axis regulation, and suggest that CST, a neuropeptide that acts through SST receptors to inhibit GH secretion, may serve a compensatory role in maintaining GH-axis function in Sst-/- male mice.
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PMID:Gender-dependent role of endogenous somatostatin in regulating growth hormone-axis function in mice. 1776 62

The neuropeptide somatostatin (SST) is expressed in a discrete population of interneurons in the dentate gyrus. These interneurons have their soma in the hilus and project to the outer molecular layer onto dendrites of dentate granule cells, adjacent to perforant path input. SST-containing interneurons are very sensitive to excitotoxicty, and thus are vulnerable to a variety of neurological diseases and insults, including epilepsy, Alzheimer's disease, traumatic brain injury, and ischemia. The SST gene contains a prototypical cyclic AMP response element (CRE) site. Such a regulatory site confers activity-dependence to the gene, such that it is turned on when neuronal activity is high. Thus SST expression is increased by pathological conditions such as seizures and by natural stimulation such as environmental enrichment. SST may play an important role in cognition by modulating the response of neurons to synaptic input. In the dentate, SST and the related peptide cortistatin (CST) reduce the likelihood of generating long-term potentiation, a cellular process involved in learning and memory. Thus these neuropeptides would increase the threshold of input required for acquisition of new memories, increasing "signal to noise" to filter out irrelevant environmental cues. The major mechanism through which SST inhibits LTP is likely through inhibition of voltage-gated Ca(2+) channels on dentate granule cell dendrites. Transgenic overexpression of CST in the dentate leads to profound deficits in spatial learning and memory, validating its role in cognitive processing. A reduction of synaptic potentiation by SST and CST in dentate may also contribute to the well-characterized antiepileptic properties of these neuropeptides. Thus SST and CST are important neuromodulators in the dentate gyrus, and disruption of this signaling system may have major impact on hippocampal function.
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PMID:Somatostatin in the dentate gyrus. 1776 24

Identification of the factors that regulate the immune tolerance and control the appearance of exacerbated inflammatory conditions is crucial for the development of new therapies of autoimmune diseases. Some neuropeptides and hormones have emerged as endogenous agents that participate in the regulation of the processes that ensure self-tolerance. Among them, cortistatin, an endogenous cyclic neuropeptide relative of somatostatin, has recently shown therapeutic potential for a variety of immune disorders. Here we examine the latest research findings, which indicate that cortistatin participates in maintaining immune tolerance in two distinct ways: by regulating the balance between pro-inflammatory and anti-inflammatory factors, and by inducing the emergence of regulatory T cells with suppressive activity against autoreactive T cell effectors.
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PMID:Emergence of cortistatin as a new immunomodulatory factor with therapeutic potential in immune disorders. 1785 Sep 53

Somatostatin receptors (sst), somatostatin (SS) and cortistatin (CST) are widely expressed in the various systems in the human and rodent organisms and are "responsible" for maintaining homeostasis, which is essential for survival. Because of their broad expression pattern sst, SS and CST interactions may play regulatory roles in both physiology and pathophysiology in mammalian organisms. SS analogue treatment strategies as well as the use of SS analogues for diagnostic purposes have been established in diseases of different origins. This review focuses on the currently determined role for SS analogues in today's clinical practice and the potential clinical prospects for SS, CST and sst interactions in the future, with a focus on neuroendocrine and non-neuroendocrine tumours and immune-mediated diseases. Moreover, the role of new SS analogues and new insights in sst physiology will be discussed.
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PMID:Future clinical prospects in somatostatin/cortistatin/somatostatin receptor field. 1794 17

Cortistatin (CST), a neuropeptide with high structural homology with somatostatin (SST), binds all SST receptor (SST-R) subtypes but, unlike SST, also shows high binding affinity to ghrelin receptor (GHS-R1a). CST exerts the same endocrine activities of SST in humans, suggesting that the activation of the SST-R might mask the potential interaction with ghrelin system. CST-8, a synthetic CST-analogue devoid of any binding affinity to SST-R but capable to bind the GHS-R1a, has been reported able to exert antagonistic effects on ghrelin actions either in vitro or in vivo in animals. We studied the effects of CST-8 (2.0 microg/kg i.v. as a bolus or 2.0 microg/kg/h i.v. as infusion) on both spontaneous and ghrelin- or hexarelin- (1.0 microg/kg i.v. as bolus) stimulated GH, PRL, ACTH and cortisol secretion in 6 normal volunteers. During saline, no change occurred in GH and PRL levels while a spontaneous ACTH and cortisol decrease was observed. As expected, both ghrelin and hexarelin stimulated GH, PRL, ACTH and cortisol secretion (p<0.05). CST-8, administered either as bolus or as continuous infusion, did not modify both spontaneous and ghrelin- or hexarelin-stimulated GH, PRL, ACTH and cortisol secretion. In conclusion, CST-8 seems devoid of any modulatory action on either spontaneous or ghrelin-stimulated somatotroph, lactotroph and corticotroph secretion in humans in vivo. These negative results do not per se exclude that, even at these doses, CST-8 might have some neuroendocrine effects after prolonged treatment or that, at higher doses, may be able to effectively antagonize ghrelin action in humans. However, these data strongly suggest that CST-8 is not a promising candidate as GHS-R1a antagonist for human studies to explore the functional interaction between ghrelin and cortistatin systems.
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PMID:Cortistatin-8, a synthetic cortistatin-derived ghrelin receptor ligand, does not modify the endocrine responses to acylated ghrelin or hexarelin in humans. 1806 63

Somatostatin (somatotropin release inhibitory factor, SRIF) and the related cortistatin (CST) are multifunctional peptide molecules attributed with neurohormone, neurotransmitter/modulator, and autocrine/paracrine actions. The physiological responses of SRIF and CST are mediated by five widely distributed G protein-coupled receptors (sst1-5) which have been implicated in regulating numerous biological processes. Much of the information on the effects of somatostatin has been gained through pharmacological studies with analogs and antagonists. The possibility of targeted mutagenesis in the mouse has resulted, over the last 10 years, in the generation of mouse models which genetically lack somatostatin ligands or receptors. We will review here the mouse models generated, the studies undertaken with them, and what has been learned so far.
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PMID:Null mutant mouse models of somatostatin and cortistatin, and their receptors. 1820 94


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