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)

Oxyntomodulin (OXM), a glucagon-containing peptide extended at its C-terminal end by an octapeptide, is a potent inhibitor of gastric acid secretion in rat and man. OXM appears to act on gastric mucosa at least partially through a stimulation of gastric somatostatin release. We have investigated the effects of OXM on a somatostatin-secreting cell line (RIN T3) derived from a radiation-induced rat insulinoma and characterized specific binding sites for this peptide. OXM increased somatostatin release with an ED50 of 2.3 nM. OXM also stimulated the cAMP accumulation in intact RIN T3 cells and adenylate cyclase activity in RIN T3 cell membranes with ED50 values of 0.5 and 11 nM, respectively. On these parameters, glucagon was 10-30 times less potent than OXM. Forskolin, isobutylmethylxanthine, and 8-bromo-cAMP mimicked the effect of OXM on somatostatin release. Specific binding for mono-[125I]OXM was dependent upon time and membrane concentration. Binding of mono-[125I]OXM was inhibited by OXM and glucagon in a concentration-dependent manner, with dissociation constants (Kd) of 4.5 and 43 nM, respectively. The nonhydrolyzable analogs of GTP (guanosine 5',3-O-(thio)triphosphate and guanosine 5' (beta,gamma-imino)triphosphate decreased the binding of mono-[125I]OXM to its binding sites. Covalent cross-linking of mono-[125I]OXM or mono-[125I]glucagon to RIN T3 cell membranes followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis demonstrated a single radiolabeled band at 63,000 mol wt, which differed from that observed after cross-linking with liver plasma membranes (55,000 mol wt). These results demonstrate the presence of specific high affinity binding sites for OXM in a somatostatin-secreting cell line (RIN T3) and their coupling to adenylate cyclase via guanine nucleotide-binding proteins.
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PMID:Characterization of binding sites for oxyntomodulin on a somatostatin-secreting cell line (RIN T3). 137 46

Somatostatin and muscarinic acetylcholine receptors are similar as far as modulation of voltage-gated Ca2+ channels and anomalously rectifying K+ channels are concerned. Activation of either type of receptors induces inhibition of Ca2+ channels and activation of anomalous K+ channels without depending on intracellular cAMP. Somatostatin appears to act on the same receptor subtype for these two actions since somatostatin receptors are homogenous in pituitary cells (Srikant and Patel, 1982; Tran et al., 1985) where the peptide produces these two effects as well as an inhibition of adenylate cyclase. In the case of muscarinic receptors, however, it remains unclear whether the same subtype of receptors is involved in both inhibition of Ca2+ channels and activation of K+ channels. Activation of muscarinic receptors in hippocampal neurones evidently produces a cAMP-independent suppression of Ca2+ channel. In cardiac cells, however, muscarinic stimulation does not cause a cAMP-independent suppression of Ca2+ channels but does activate an anomalous rectifier. These findings do not necessarily mean that the muscarinic receptor involved in the inhibition of Ca2+ channels in hippocampal neurones is not of m2 type which is assumed to mediate the activation of anomalous K+ channels in cardiac cells. There is no evidence that cardiac Ca2+ channels are identical to hippocampal Ca2+ channels susceptible to muscarinic inhibition. In addition, a similar argument could be applied to G proteins coupling muscarinic receptors to Ca2+ channels in neurones and cardiac myocytes. In this regard, it should be noted that activation of GABAB receptors or mu and delta opiate receptors, an event known to inhibit adenylate cyclase activity through a PTX-sensitive Gi protein, also produces both inhibition of Ca2+ channels and activation of anomalous K channels in a cAMP-independent manner. This close correlation between inhibition of adenylate cyclase activity and cAMP-independent modulation of Ca2+ and K+ channels suggests the possible involvement of m2 subtype in the inhibition of Ca2+ channels in hippocampal neurones. Circumstantial evidence indicates that anomalous K+ channels are directly activated by alpha subunits of Gi, but not Go, proteins. The alpha subunit of Go protein seems to mediate inhibition of the Ca2+ channel, probably in a direct manner. The most striking difference between somatostatin and muscarinic receptors would be their opposite actions on the M channel. All the inhibitory receptors on the M channel, including m1 and m3 receptors, are known to stimulate PI hydrolysis via a PTX-insensitive G protein.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Modulation of ion channels by somatostatin and acetylcholine. 137 25

In recent years there has been an increased interest in understanding the role of somatostatin in the brain. This review summarizes the current knowledge of the anatomical distribution of somatostatin and its receptors, the receptor-coupling mechanisms and the somatostatinergic modulation of cognitive functions. Somatostatin is also highly concentrated in the extra-hypothalamic areas of the brain, including the frontal and parietal cortex and the hippocampus. At these locations somatostatin may play a fundamental role in the modulation of cognitive functions. Activation of somatostatin receptors in the brain results in an inhibition of adenylate cyclase enzyme activity, reduction in intracellular Ca2+ levels and hypopolarization of cells by inducing outward K+ currents. Biological studies on the effects of increased brain somatostatin showed a facilitation in learning behavioural tasks, while brain somatostatin depletion by cysteamine caused memory loss. These observations, along with the severe somatostatinergic neurotransmission impairment demonstrated in Alzheimer's patients, strongly suggest a fundamental role for somatostatin in the modulation of cognitive functions.
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PMID:Brain somatostatin: receptor-coupled transducing mechanisms and role in cognitive functions. 164 19

Morphine and ethanol drugs known to develop tolerance and dependence, induce changes in the adenylate cyclase system. Morphine inhibits the adenylate cyclase activity in NG108-15 cells and causes increases in adenylate cyclase synthesis and the down-regulation of opiate receptors in cells treated for several days. Chronic exposure of NG108-15 cells to ethanol also causes a decrease in the mRNA of the GTP-binding protein (Gs). These observations suggest the possibility that a group of genes is expressed in response to morphine or ethanol during the acquisition of tolerance and dependence. Recently, it has been reported that cAMP regulates a number of genes through a cAMP response element (CRE) in their promotor regions and that nuclear CRE-binding proteins bind specifically to the CRE to stimulate the transcription of cAMP-responsive genes. The gel shift assay with a single stranded oligo-DNA of CRE in a somatostatin promotor region was employed to examine the possibility of transcriptional regulation of cAMP-inducible genes by chronic morphine or ethanol treatment of NG108-15 cells. When the nuclear proteins from the cells treated with morphine or ethanol for several days were provided for the assay, the amounts of DNA-protein complex were decreased. The decreased complexes were recovered by 1-2 days after morphine withdrawal. The nuclear proteins were purified partially by a combination of chromatography on Q-Sepharose, Sephacryl S-300 and DNA affinity-Sepharose. Changes in CRE-binding proteins from the cells treated chronically with morphine or ethanol suggest that these drugs can modulate the expression of cAMP-inducible genes through which tolerance and dependence may develop.
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PMID:[Molecular mechanism of drug tolerance and dependence]. 166 Apr 43

In recent years evidence has accumulated indicating the presence of functional receptors for most neurotransmitters on astrocytes. In particular, receptors coupled to adenylate cyclase have been demonstrated, in primary astrocyte cultures, for vasoactive intestinal peptide (VIP), noradrenaline (NA) and adenosine. Here we provide, in primary cultures of cerebral cortical astrocytes prepared from neonatal mice, a detailed characterization of a cAMP-dependent process elicited by VIP, NA and adenosine, i.e. the hydrolysis of glycogen. The EC50s for the glycogenolytic effect of VIP, NA and adenosine are 3, 20 and 800 nM, respectively. The initial rate of glycogen hydrolysis is, in nmol/mg prot/min, 9.1 for VIP and 7.5 for NA. The effect of NA is predominantly mediated by beta-adrenoceptors, although an alpha 1-adrenergic component, acting most likely through protein kinase C activation, is also present. The action of VIP is mimicked by peptides sharing sequence homologies such as PHI and secretin. Glutamate, GABA, carbachol and the peptides NPY and somatostatin do not influence glycogen levels. The glycogen content of the cultures can be markedly increased by anabolic factors present in fetal calf serum, by high (e.g. 25 mM) glucose in the medium and by 48-h pretreatment of the cultures with dibutyryl cAMP. These results indicate that the glycogen content of astrocytes is under the dynamic control of various factors, including certain neurotransmitters. They also further stress the notion of a functional interaction between neurons and glial cells aimed at maintaining local energy metabolism homeostasis.
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PMID:Characterization of the glycogenolysis elicited by vasoactive intestinal peptide, noradrenaline and adenosine in primary cultures of mouse cerebral cortical astrocytes. 166 73

The direct action of somatostatin on smooth muscle was examined in muscle cells isolated from the stomach and intestine of human and guinea pig. Somatostatin inhibited relaxation in gastric but not intestinal muscle cells of the two species, and its mechanism of action was explored in more detail in gastric muscle cells of the guinea pig. Somatostatin inhibited relaxation induced by vasoactive intestinal peptide (VIP, 83 +/- 7%, P less than 0.001) and isoproterenol (85 +/- 5%, P less than 0.001), as well as the concomitant increase in adenosine 3',5'-cyclic monophosphate (cAMP) production [81 +/- 25% inhibition with VIP (P less than 0.02) and 68 +/- 12% inhibition with isoproterenol (P less than 0.01)]. Inhibition of relaxation and cAMP production was abolished by pretreatment of the cells with pertussis toxin. Relaxation induced by the permeant derivative of cAMP, N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate, by sodium nitroprusside, which acts by increasing levels of guanosine 3',5'-cyclic monophosphate, or by ATP, which acts by opening of K+ channels, was not affected by somatostatin. The fact that inhibition by somatostatin and its reversal by pertussis toxin was confined to agonists that stimulate an increase in the levels of cAMP implied that somatostatin acts by inhibiting the generation and not the action of cAMP. It is concluded that somatostatin receptors on gastric muscle cells mediate inhibition via a GTP-binding, pertussis-sensitive regulatory protein, Gi, coupled to adenylate cyclase.
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PMID:Inhibition of muscle cell relaxation by somatostatin: tissue-specific, cAMP-dependent, pertussis toxin-sensitive. 167 35

Frog esophageal mucosa contains peptide glands which release pepsinogen in response to a variety of secretagogues and serves as a model to examine the inhibitory action of somatostatin. The pepsinogen secretion in response to bethanechol was inhibited by somatostatin in a noncompetitive fashion. The maximal response induced by bethanechol was reduced and the EC50 for bethanechol was increased in the presence of somatostatin. On the other hand, somatostatin showed essentially no effect on pepsinogen release evoked by ionophore A23187, dibutyryl cAMP or by forskolin in the presence of atropine. Atropine was included in the incubation mixture to eliminate the effect of acetylcholine released by forskolin from the intrinsic cholinergic neurons also present in the mucosa. Somatostatin did not exert any significant effect on the basal or the forskolin-stimulated cAMP accumulation in the mucosa, nor the basal or the forskolin-stimulated adenylate cyclase activity in the membranes of the peptic cells isolated from the mucosa. Thus, these results seem to suggest that somatostatin inhibits pepsinogen secretion from frog esophageal mucosa by a cAMP-independent pathway.
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PMID:Somatostatin inhibits pepsinogen secretion via a cyclic AMP-independent pathway. 167 98

The role of signal transduction systems was examined in the secretion of GH-releasing hormone (GHRH) and somatostatin (SS) from perifused rat hypothalamic fragments. Forskolin, an adenylate cyclase activator, stimulated the release of GHRH and SS in a concentration-dependent manner (10-100 microM) with greatest stimulation for GHRH at 100 microM (mean +/- SE, 249 +/- 14%) and for SS at 30 microM (172 +/- 18%). (Bu)2cAMP also augmented GHRH and SS release. The protein kinase-C activator phorbol 12-myristate 13-acetate did not significantly stimulate basal GHRH or SS release at concentrations of 10 nM to 1 microM. The calcium ionophore A23187 enhanced the release of GHRH and SS in a concentration-dependent manner (2-20 microM), with the greatest responses of 282 +/- 50% at 10 microM and 189 +/- 24% at 20 microM, respectively. Potentiation by phorbol 12-myristate 13-acetate of forskolin-stimulated GHRH and SS release was observed. A23187 at 10 microM did not enhance forskolin-stimulated GHRH release, but did potentiate forskolin-stimulated SS release in a more than additive response. We conclude that there is 1) cAMP stimulation of hypothalamic GHRH and SS release, 2) a modulating role of protein kinase-C on cAMP-stimulated release of GHRH and SS, 3) a stimulatory role of the calcium messenger system for GHRH and SS release, 4) interaction of the signal pathways with differences in net GHRH and SS responses, and 5) a modulatory effect of protein kinase-C in perifused hypothalamic fragments which differs from the stimulation of basal GHRH and SS release reported in fetal-derived hypothalamic cell cultures. Our observations suggest an important regulatory role of interacting signal transduction systems in the hypothalamic secretion of GHRH and SS.
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PMID:Signal transduction systems in growth hormone-releasing hormone and somatostatin release from perifused rat hypothalamic fragments. 167 98

To investigate whether somatostatin (SRIF) receptor subpopulations mediate different physiological actions of SRIF, we tested the effects of SRIF and the SRIF agonists MK 678 and CGP 23996 on different biological responses in rat neocortical neurons in culture. Neocortical cells in culture express SRIF receptors that can be labeled with 125I-MK 678 and 125I-CGP 23996. Pharmacological analysis of the binding sites indicates that the radioligands label SRIF receptor subtypes with distinct pharmacological characteristics. These receptor subpopulations are similar to those expressed in adult rat brain. SRIF, MK 678, and CGP 23996 are able to inhibit forskolin-stimulated adenylate cyclase activity in rat neocortical membranes by 25-30%. Furthermore, they inhibit a high voltage-activated Ca2+ current in rat neocortical neurons in culture by 25-35%. Both SRIF and MK 678 potentiate a delayed rectifier K+ current in rat neocortical neurons in culture by 25-30%. In contrast, high concentrations of CGP 23996 do not alter the K+ current. In cells that do not respond to CGP 23996, MK 678 increases the delayed rectifier K+ current. The findings of these studies indicate that rat neocortical neurons in culture express functionally distinct SRIF receptor subtypes that can be differentially activated by SRIF agonists.
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PMID:Subtypes of brain somatostatin receptors couple to multiple cellular effector systems. 167 52

Adenosine is a potent paracrine/autocrine feedback inhibitor of cell activation in a variety of tissues. Adenosine action was studied in pituitary cells, in which spontaneous electrical activity causes characteristic oscillations of the cytosolic free Ca2+ concentration, [Ca2+]i. Cells of the GH3B6 rat pituitary tumor line were studied by microspectrofluorimetry using the Ca2+ probes indo-1 and fura-2, in part in combination with electrophysiological tight seal whole cell recordings, obtained with the novel approach of patch perforation. It was demonstrated that adenosine receptor activation by N6-(R-phenyl-isopropyl)-adenosine (PIA) caused a block of electrical activity and abolished the ensuing alterations in [Ca2+]i. PIA mimicked the inhibitory action of somatostatin. Adenosine effects are mediated by A1 receptors in these cells and are antagonized by IBMX, an adenosine receptor blocker. PIA also suppressed action potentials that were elicited by the activation of protein kinase C with the phorbol ester PMA, or during the second phase of TRH action. In contrast, no interference was notable on TRH-induced intracellular Ca2+ mobilization. In addition to the abolition of Ca2+ transients, PIA lowers basal [Ca2+]i in some cells. It is proposed that in addition to the inhibition of adenylate cyclase, A1 receptor action on [Ca2+]i is an important element in the control of excitable pituitary cells.
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PMID:Adenosine A1 receptor-induced inhibition of Ca2+ transients linked to action potentials in clonal pituitary cells. 168 Jul 18


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