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)

Acetylcholine (ACh) plays a key role in the transitions between the different phases of sleep: Slow-wave sleep requires low ACh concentrations in the brain, whereas rapid-eye-movement (REM) sleep is associated with high levels of ACh. Also, these phases of sleep are differentially sensitive to a number of endogenous neuropeptides and cytokines, including somatostatin, which has been shown to increase REM sleep without significantly affecting other phases. Here we report the cloning and initial characterization of cortistatin, a neuropeptide that exhibits strong structural similarity to somatostatin, although it is the product of a different gene. Administration of cortistatin depresses neuronal electrical activity but, unlike somatostatin, induces low-frequency waves in the cerebral cortex and antagonizes the effects of acetylcholine on hippocampal and cortical measures of excitability. This suggests a mechanism for cortical synchronization related to sleep.
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PMID:A cortical neuropeptide with neuronal depressant and sleep-modulating properties. 862 67

Recent advances in the fields of molecular cloning and peptide purification necessitate a reappraisal of our views concerning the evolution of the genes encoding somatostatin-related peptides. The currently widely held view that the genomes of tetrapods contain only the preprosomatostatin-I (PSS-I) gene, encoding somatostatin-14, with a second preprosomatostatin gene being expressed only in teleost fish is no longer tenable. Identification of genes encoding both somatostatin-14 and the somatostatin-related peptide, cortistatin in mammals, identification of the PSS-I and PSS-II preprosomatostatin genes in amphibia, and the isolation of gene products from at least two non-allelic preprosomatostatin genes in lampreys suggests the alternative hypothesis that duplication of the PSS-I gene occurred early in evolution, predating or concomitant with the appearance of the chordates. We speculate that at least two somatostatin genes are expressed in all classes of vertebrates but these genes have evolved at very different rates. It is probable that the preprosomatostatin-II (PSS-II) gene, encoding [Tyr7, Gly10] somatostatin-14 or a related peptide, arose from a second independent duplication of the PSS-I gene in the ancestor of present-day teleost fish at a time after the divergence of the teleost stock from the line of evolution leading to tetrapods. The recent isolation of urotensin II, a peptide which contains a region of structural similarity but is not evolutionarily related to somatostatin-14, from the central nervous systems of lampreys, elasmobranchs and amphibia necessitates that we modify the accepted view that urotensin II is exclusively a product of the caudal neurosecretory system of teleost fish.
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PMID:Somatostatin- and urotensin II-related peptides: molecular diversity and evolutionary perspectives. 917 52

Cortistatin is a 14-residue putative neuropeptide with strong structural similarity to somatostatin and is expressed predominantly in cortical GABAergic interneurons of rats. Administration of cortistatin into the brain ventricles specifically enhances slow-wave sleep, presumably by antagonizing the effects of acetylcholine on cortical excitability. Here we report the identification of cDNAs corresponding to mouse and human preprocortistatin and the mRNA distribution and gene mapping of mouse cortistatin. Analysis of the nucleotide and predicted amino acid sequences from rat and mouse reveals that the 14 C-terminal residues of preprocortistatin, which make up the sequence that is most similar to somatostatin, are conserved between species. Lack of conservation of other dibasic amino acid residues whose cleavage by prohormone convertases would give rise to additional peptides suggests that cortistatin-14 is the only active peptide derived from the precursor. As in the rat, mouse preprocortistatin mRNA is present in GABAergic interneurons in the cerebral cortex and hippocampus. The preprocortistatin gene maps to mouse chromosome 4, in a region showing conserved synteny with human 1p36. The human putative cortistatin peptide has an arginine for lysine substitution, compared to the rat and mouse products, and is N-terminally extended by 3 amino acids.
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PMID:Cloning, mRNA expression, and chromosomal mapping of mouse and human preprocortistatin. 920 24

Cortistatin is a presumptive neuropeptide that shares 11 of its 14 amino acids with somatostatin. In contrast to somatostatin, administration of cortistatin into the rat brain ventricles specifically enhances slow wave sleep, apparently by antagonizing the effects of acetylcholine on cortical excitability. Here we show that preprocortistatin mRNA is expressed in a subset of GABAergic cells in the cortex and hippocampus that partially overlap with those containing somatostatin. A significant percentage of cortistatin-positive neurons is also positive for parvalbumin. In contrast, no colocalization was found between cortistatin and calretinin, cholecystokinin, or vasoactive intestinal peptide. During development there is a transient increase in cortistatin-expressing cells in the second postnatal week in all cortical areas and in the dentate gyrus. A transient expression of preprocortistatin mRNA in the hilar region at P16 is paralleled by electrophysiological changes in dentate granule cells. Together, these observations suggest mechanisms by which cortistatin may regulate cortical activity.
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PMID:Cortistatin is expressed in a distinct subset of cortical interneurons. 922 84

1. In this study we examined the effects of cortistatin, a putative endogenous ligand for somatostatin (SRIF) receptors, on the membrane properties of rat locus coeruleus (LC) neurones in vitro, by use of intracellular and whole cell patch clamp recording. We have compared the actions of cortistatin with those of SRIF and the SRIF analogue D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP). 2. When LC neurones were voltage clamped to -60 mV, application of cortistatin caused an outward current in all cells examined (n = 44), with a pEC50 of 6.62. SRIF also caused an outward current in all cells examined (n = 43), with a pEC50 of 6.93. 3. The outward currents caused by cortistatin in 2.5 mM extracellular K+ reversed polarity at -106 mV, very close to the predicted K+ reversal potential of -105 mV. Increasing extracellular K+ to 10.5 mM resulted in a shift of the reversal potential of +38 mV, a shift consistent with a K+ conductance. The conductance activated by cortistatin showed mild inward rectification. 4. Continuous application of a high concentration of SRIF (1 microM) resulted in a decrease of the outward current to a steady level of 49% of the maximum response, with a t1/2 of 131 s. Application of a high concentration of cortistatin (3 microM) during the desensitized portion of the SRIF response did not result in any further outward current. Continuous application of a high concentration of cortistatin (10 microM) resulted in a decrease of the outward current to a steady level of 42% of the maximum response with a t1/2 of 114 s. Application of a high concentration of SRIF (3 microM) during the desensitized portion of the cortistatin response produced only a small outward current. 5. Continuous application of cortistatin (3 microM) also resulted in a decrease of the outward current (by 43%, t1/2 of 136 s) and application of a high concentration of CTOP (10 microM) during the desensitized portion of the cortistatin response did not produce any outward current. Continuous application of a high concentration of CTOP (10 microM) resulted in a decrease of the outward current to a steady level of 70% of the maximum response with a t1/2 of 143 s. Application of a high concentration of cortistatin (3 microM) during the desensitized portion of the CTOP response did not result in any further outward current. 6. The actions of cortistatin (300 nM-10 microM) were not affected by the opioid antagonist naloxone (10 microM). Application of met-enkephalin during the desensitized portion of the response to a high concentration of cortistatin (3 microM) produced an outward current similar to that produced by metenkephalin application alone. 7. Thus cortistatin efficaciously activates an inwardly rectifying K+ conductance in LC neurones. These actions appear to be mediated by a population of SRIF receptors, at which CTOP is also an agonist. Cortistatin does not appear to be a ligand for mu-opioid receptors in rat LC neurons.
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PMID:Cortistatin increase of a potassium conductance in rat locus coeruleus in vitro. 942

The recently cloned rat preprocortistatin, which shows homology to the preprosomatostatin peptide, is thought to be enzymatically cleaved to cortistatin14 (CST14) similarly to somatostatin14 (SRIF14). High structural similarity of cortistatin14 compared to SRIF14 suggested binding properties to somatostatin receptors similar to SRIF14. In the present study, we expressed stably the five human somatostatin receptor subtypes (hsst1-hsst5) in CCL39 cells (Chinese hamster lung fibroblast cells). The receptors were labelled with an iodinated analogue of CST14 ([125I]Tyr10)-cortistatin14, [125I]Tyr10-CST) to establish the pharmacological profile of hsst1-hsst5 sites labelled with [125I]Tyr10-CST. In parallel, [Leu8,D-Trp22,125I-Tyr25]-SRIF28 ([125I]LTT-SRIF28) was used as a control at the five recombinant SRIF receptors stably expressed in CCL39 cells. High affinity [125I]Tyr10-CST binding could be demonstrated to all five recombinant somatostatin receptor subtypes. The pKd (-log mol/l) and Bmax values (fmol/mg) for hsst1-5 receptors were: 10.02+/-0.04, 220+/-30; 9.45+/-0.09, 340+/-70; 10.06+/-0.11, 340+/-50; 9.67+/-0.14, 340+/-110 and 10.33+/-0.03, 5630+/-1330, respectively. The pharmacological profiles determined with [125I]Tyr10-CST and [125I]LTT-SRIF28 were very similar at every receptor studied. These data suggest that cortistatin and somatostatin have similar high affinity for SRIF receptors. None of the receptors showed marked selectivity for either CST14/CST17 or the somatostatins. In conclusion, the data show that cortistatin and somatostatin have very similar high affinity to all five recombinant somatostatin receptors. It remains to be seen whether there are specific receptors which bind only somatostatins or cortistatins.
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PMID:[125I]Tyr10-cortistatin14 labels all five somatostatin receptors. 965 Jul 99

Cortistatin (CST-14) is a recently discovered endogenous peptide which shares similarity to somatostatin and binds to somatostatin receptors. In this study, we show that CST-14 exhibits anticonvulsive and neuroprotective effects in rats. Injection of rats with kainic acid (KA; 10 mg/kg; i.p.) generated a strong seizure activity which was attenuated by the i.c.v. application of 1 and 10 nmol CST-14 when given 10 min before KA. Moreover, 3 days after KA injection, a marked loss of neurons in cortex and hippocampus of rats was observed which was inhibited by pretreatment with CST-14. An immunohistochemical analysis using specific antibodies revealed that KA reduced immunoactive sst2A and sst3 somatostatin receptors in the hippocampus-an effect which was largely prevented by pretreatment with CST-14. Superfusion of hippocampal slices with CST-14 also reduced the stimulated release of 3H-d-aspartate. We conclude that CST-14 exerts neuroprotective effects by binding to somatostatin receptors which in turn leads to a reduced release of excitotoxic neurotransmitters.
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PMID:Protective effects of cortistatin (CST-14) against kainate-induced neurotoxicity in rat brain. 972 75

We measured somatostatin-like immunoreactivity, using a radioimmunoassay which does not cross react with cortistatin-like immunoreactivity, in postmortem frontal cortex (Brodmann area 9) from 32 patients, of different apolipoprotein E genotypes, and presenting with different degrees of cognitive impairment. Eleven subjects and eight patients presented with no (controls) or limited memory impairments (Borderline), respectively. Six patients with clinical criteria for possible Alzheimer's disease also presented with clinical or brain imaging of cerebrovascular disease (mixed dementia) and seven patients were classified as Alzheimer's disease (AD). In the 6 months preceeding their deaths, all subjects had been evaluated by Folstein's Mini Mental State examination (MMS). Sixty nine percent of patients with MMS >20 did not carry the epsilon 4 allele while 66% of patients with MMS <10 did. Somatostatin concentrations (ng/mg wet weight) were significantly lower in the patients carrying the epsilon 4 allele (E2/3: 0.71 +/- 0.05, n = 19 vs. E4: 0.42 +/- 0.06, n = 13; mean +/- SEM, P < 0.001). These results, which are reminiscent of those obtained on cholinergic markers, suggest that apolipoprotein E4 is involved in the somatostatinergic dysfunction early after the onset in AD.
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PMID:Loss of somatostatin-like immunoreactivity in the frontal cortex of Alzheimer patients carrying the apolipoprotein epsilon 4 allele. 983 17

Somatostatin (SRIF) was discovered in 1973, in Roger Guillemin's laboratory as a Growth Hormone (GH) inhibiting neurohormone. It is widely distributed in mammals where it acts also as a peripheral hormone, an autocrine or paracrine factor and a neuropeptide. SRIF receptors are located on several human tumours and SRIF agonists are in clinical use to monitor GH secretion in acromegalic patients. This short review summarizes the properties of the central and peripheral somatostatinergic systems, the three peptides belonging to the somatostatin family: (SRIF14, SRIF28 and cortistatin), the pharmacology of the five SRIF receptor subtypes, some ontogenetic and phylogenetic aspects, as well as pathological findings.
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PMID:[Somatostatin: a ubiquitous peptide]. 984 66

Cortistatin is a 14-residue putative neuropeptide with strong structural similarity to somatostatin. Even if it shares several biological properties with somatostatin, the effects of cortistatin on cortical electrical activity and sleep are opposite to those elicited by somatostatin. We recently demonstrated that somatostatin could modulate glutamate sensitivity, either positively through activation of the sstl receptor subtype, or negatively through activation of the sst2 receptor subtype in hypothalamic neurons in culture which express almost exclusively these two sst subtypes. Thus, in the present study we compared the effects of cortistatin and somatostatin in hypothalamic neurons in culture, in order to define the former peptide activity on both subtypes. We first determined that the affinities of cortistatin and somatostatin were similar on cloned rat sstl and sst2 receptor subtypes in transfected cells and hypothalamic neurons membranes. We then found that cortistatin, like somatostatin, depresses the glutamate response but, unlike somatostatin, never potentiates glutamate sensitivity in hypothalamic neurons. The observed effect of cortistatin is strongly suggestive of an activation of the somatostatin sst2 receptor subtype in hypothalamic neurons in culture.
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PMID:Cortistatin affects glutamate sensitivity in mouse hypothalamic neurons through activation of sst2 somatostatin receptor subtype. 1019 59


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