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)

The phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and thyroliberin exerted additive stimulatory effects on prolactin release and synthesis in rat adenoma GH4C1 pituicytes in culture. Both TPA and thyroliberin activated the adenylate cyclase in broken cell membranes. When combined, the secretagogues displayed additive effects. TPA did not alter the time course (time lag) of adenylate cyclase activation by hormones, guanosine 5'-[beta,gamma-imino]triphosphate or forskolin, nor did it affect the enzyme's apparent affinity (basal, 7.2 mM; thyroliberin-enhanced, 2.2 mM) for free Mg2+. The TPA-mediated adenylate cyclase activation was entirely dependent on exogenously added guanosine triphosphate. ED50 (dose yielding half-maximal activation) was 60 microM. Access to free Ca2+ was necessary to express TPA activation of the enzyme, however, the presence of calmodulin was not mandatory. TPA-stimulated adenylate cyclase activity was abolished by the biologically inactive phorbol ester, 4 alpha-phorbol didecanoate, by the protein kinase C inhibitor polymyxin B and by pertussis toxin, while thyroliberin-sensitive adenylate cyclase remained unaffected. Experimental conditions known to translocate protein kinase C to the plasma membrane and without inducing adenylate cyclase desensitization, increased both basal and thyroliberin-stimulated enzyme activities, while absolute TPA-enhanced adenylate cyclase was maintained. Association of extracted GTP-binding inhibitory protein, Gi, from S49 cyc- murine lymphoma cells with GH4C1 cell membranes yielded a reduction of basal and hormone-stimulated adenylate cyclase activities, while net inhibition of the cyclase of somatostatin was dramatically enhanced. However, TPA restored completely basal and hormone-elicited adenylate cyclase activities in the Gi-enriched membranes. Finally, TPA completely abolished the somatostatin-induced inhibition of adenylate cyclase in both hybrid and non-hybrid membranes. These data suggest that, in GH4C1 cells, protein kinase C stimulation by phorbol esters completely inactivates the n alpha i subunit of the inhibitory GTP-binding protein, leaving the n beta subunit functionally intact. It can also be inferred that thyroliberin conveys its main effect on the adenylate cyclase through activation of the stimulatory GTP-binding protein, Gs.
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PMID:Protein kinase C stimulates adenylate cyclase activity in prolactin-secreting rat adenoma (GH4C1) pituicytes by inactivating the inhibitory GTP-binding protein Gi. 256 96

In experiments using a synaptosomal preparation from the striatum and nucleus accumbens, somatostatin caused a dose-dependent increase in dopamine synthesis. This increase was additive with that produced by 8-BrcAMP but not with that produced by the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate (TPA), and was blocked by the protein kinase C inhibitor polymyxin B (PMB). These findings suggest that stimulation of dopamine synthesis by somatostatin is mediated by activation of protein kinase C.
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PMID:Protein kinase C mediates the stimulation by somatostatin of dopamine synthesis in the rat striatum and nucleus accumbens. 289 60

Hormonal activation and inhibition of the GH4Cl1 cell adenylate cyclase complex is delineated. In the presence of the guanyl nucleotide GTP, enzyme activity was enhanced twofold by thyroliberin, sixfold by vasoactive intestinal peptide (VIP), twofold by prostaglandin E2 and twofold by isoproterenol. The diterpene, forskolin, increased, the activity 14-fold. In the presence of high GTP (400 microM) and NaCl (150 mM) concentrations, somatostatin inhibited (ED50 = 0.5 microM) the cyclase activity by 40%. In the presence of 10 microM somatostatin, the ED50 values (5 nM) for thyroliberin- and VIP-stimulated adenylate cyclase activities were shifted to 20 nM. Forskolin-elicited activation was, however, not affected by somatostatin. Cholera-toxin and pertussis-toxin pretreatment of the enzyme brought about some 20-fold and twofold activation, respectively. Inhibition by somatostatin was abolished upon pre-exposure to pertussis toxin. Mild alkylation by N-ethylmaleimide increased basal and hormone-activated adenylate cyclase while somatostatin again failed to express its inhibitory potential. Further alkylation caused a gradual decline and convergence of hormone-modulated cyclase activities towards zero. The N-ethylmaleimide-induced attenuation of thyroliberin-elicited activity was paralleled by a decrease in [3H]thyroliberin binding. Trifluoperazine and an anti-calmodulin serum reduced basal and net thyroliberin-, VIP- and forskolin-enhanced cyclase activities by some 30%, 100%, 70% and 80%, respectively. The Vmax of basal and thyroliberin-stimulated adenylate cyclase was diminished by 65%, leaving the apparent Km values (7.2 mM and 2.6 mM, respectively) for Mg2+ unaltered. Finally, the phorbol ester 12-O-tetra-decanoyl-phorbol 13-acetate (TPA) doubled the activity. This effect was counteracted by the protein kinase C inhibitor, polymyxin B, while thyroliberin-enhanced adenylate cyclase remained unaffected. In summary, we have described an adenylate cyclase with stimulatory (Rs) and inhibitory (Ri) receptors coupled to a calmodulin-sensitive holoenzyme through the Gs and Gi type of GTP-binding proteins. The ratio of the Gs to Gi is high. It appears that the GH4C1 cell adenylate cyclase is also activated by protein kinase C by interference with Gi. Apparently, thyroliberin activates the cyclase both directly through Gs and indirectly via protein kinase C stimulation.
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PMID:Hormone-sensitive adenylate cyclase of prolactin-producing rat pituitary adenoma (GH4C1) cells: molecular organization. 290 68

In vitro exposure of rat cerebrocortical slices to microM concentrations of serotonin (5HT) results in an increased response of adenylate cyclase to isoproterenol (ISO). No change in the affinity of the beta-adrenoceptor toward the agonist was found after 5HT exposure when measuring ISO displacement of [3H]CGP 12177 binding. A similar increase of adenylate cyclase response was also found when using VIP as a stimulatory agent. The dose-response curve of adenylate cyclase to the GTP analogue, GppNHp, was modified by 5HT, which promotes a significantly higher maximal response without altering the potency of GppNHp. Forskolin-stimulated adenylate cyclase activity was not affected by 5HT. Serotonergic 5HT2 receptors are involved in the sensitization of adenylate cyclase to GppNHp, since the selective 5HT2 antagonist ketanserin inhibits the effect of 5HT, whereas the 5HT2 agonist DOI mimics 5HT. The involvement of 5HT2 receptor-coupled activation of protein kinase C is also demonstrated: direct protein kinase C activators such as phorbol esters and s,n-dioctanoylglycerol behave in the same manner as 5HT, while the protein kinase C inhibitor CGP 41251 prevents 5HT from increasing adenylate cyclase responsiveness to GppNHp. Moreover, in vitro exposure of cortical slices to 5HT results in reduced inhibition of adenylate cyclase by somatostatin. Since no change was observed at the receptor level and in the direct stimulation of the catalytic subunit of the enzyme, we propose that 5HT might accomplish the sensitization of adenylate cyclase through protein kinase C by inactivating the inhibitory coupling protein Gi and facilitating the interaction of the exogenous GppNHp with the stimulatory coupling protein Gs.
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PMID:Heterologous sensitization of adenylate cyclase activity by serotonin in the rat cerebral cortex. 790 77

The effects of various neuropeptides on human plasma cells were studied. Of the various neuropeptides tested, vasoactive intestinal peptide (VIP) enhanced Ig production and growth in human plasma cell lines, IM-9 and AF-10, and in plasma cells generated in vivo (four out of four patients with plasma cell leukemia) and in vitro. In contrast, other neuropeptides (neuropeptide Y, somatostatin, substance P, peptide YY, neurokinin A, calcitonin gene-related peptide, chole-cystokinin octapeptide, and beta-endorphin) were ineffective. Moreover, VIP-induced enhancement was specifically blocked by VIP receptor antagonist. Among the various cytokines, IL-6, GH, and insulin-like growth factor I (IGF-I) also enhanced Ig production and thymidine uptake in plasma cells. However, VIP-induced enhancement was not mediated by IL-6, GH, or IGF-I because antibodies to these cytokines failed to block VIP-induced enhancement. Phorbol 12,13 dibutyrate enhanced Ig production and thymidine uptake in plasma cells, and the Phorbol 12,13 dibutyrate-induced enhancement was blocked by H7 (a protein kinase C inhibitor) but not by H8 (a protein kinase A inhibitor). Similarly, VIP-induced enhancement was blocked by H7 but not by H8. Collectively, VIP enhances plasma cell responses via mechanisms that may involve protein kinase C.
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PMID:Vasoactive intestinal peptide enhances immunoglobulin production and growth in human plasma cells via mechanisms that may involve protein kinase C. 876 69

Polybasic secretagogues such as mastoparan, compound 48/80, substance P, and somatostatin stimulate secretion in rat peritoneal mast cells through direct activation of the heterotrimeric G protein, G(i-3). Cultured RBL-2H3 mast cells do not normally respond to these secretagogues, but, as reported here, they do so after prolonged exposure to the kinase inhibitor, quercetin. This inhibitor, which causes phenotypic changes in RBL-2H3 cells, induces a substantial increase (more than sevenfold) in the expression of alpha subunits of the pertussis toxin-sensitive G proteins, G(i-2) and G(i-3). Compound 48/80-induced secretion is associated with transient hydrolysis of phosphoinositides and a transient increase in cytosolic calcium ions. These responses are inhibited by pertussis toxin, and in addition, secretion is blocked by calcium chelation and the protein kinase C inhibitor, Ro31-7549. These results delineate a pathway for compound 48/80-induced secretion in mast cells via Gi protein(s), phospholipase C, calcium, and protein kinase C. The results also imply that phospholipase C, most likely phospholipase Cbeta3, can be transiently activated in RBL-2H3 cells by subunits of Gi proteins to induce cellular responses.
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PMID:Quercetin sensitizes RBL-2H3 cells to polybasic mast cell secretagogues through increased expression of Gi GTP-binding proteins linked to a phospholipase C signaling pathway. 959 Feb 66

We have studied the mechanism of soybean agglutinin (SBA) mediated cholecystokinin (CCK) release in enriched cultured cholecystokinin-secreting cells. 12-O-Tetradecanoylphorbol-13-acetate 1 mM significantly stimulated release of CCK-like-immunoreactivity (CCK-LI) by 55%+/-17% (p < 0.05), which was blocked by the protein kinase C inhibitor staurosporine 100 nM. Forskolin 10 mM stimulated CCK-LI by 82%+/-12% (p < 0.05) and this was inhibited by somatostatin 1 nM. 1-Phenylalanine 20 mM and Bay K 8644 1 mM stimulated CCK-LI by 69%+/-22% and 60%+/-19% respectively (p < 0.05), these responses were completely abolished by the L-type calcium channel antagonist verapamil 10 mM. SBA 10 and 100 microg/ml stimulated CCK-LI by 65%+/-22% and 74%+/-24% respectively (p < 0.05). The effect of SBA was inhibited by verapamil and N-acetylgalactosamine. We conclude that SBA stimulates CCK-LI through calcium flux via L-type calcium channels.
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PMID:Soybean agglutinin stimulated cholecystokinin release from cultured rabbit jejunal cells requires calcium influx via L-type calcium channels. 986 61

CGP 36742 is a weak GABA(B) receptor antagonist. However, it improves cognitive performances at low doses; it blocks GABA(B) receptors potently and selectively on somatostatinergic terminals; it prevents kynurenate from antagonising NMDA-induced release of noradrenaline from rat brain slices potently. We here investigated whether and how somatostatin plays a role in the CGP 36742 activity. CGP 36742 increased the somatostatin-like immunoreactivity (SRIF-LI) release from hippocampal slices exposed to NMDA. In the kynurenate test with rat hippocampal slices SRIF-14 mimicked the effect of CGP 36742. CGP 36742 lost its activity in rats whose somatostatin content had been depleted with cysteamine. Exogenous SRIF-14 reverted kynurenate antagonism in somatostatin-depleted slices. L362855, an sst(5) receptor agonist, but not the selective sst(1)-sst(4) agonists, L797591, L779976, L796778 and L803087, displayed activity in the kynurenate test. The effects of CGP 36742, SRIF-14 and L362855 were antagonised by the sst(5)-preferring antagonist BIM-23056. The protein kinase C inhibitor GF 109203X prevented the reversal of the kynurenate antagonism by CGP 36742 or SRIF-14. In conclusion, by selectively blocking GABA(B) receptors on somatostatinergic terminals, CGP 36742 may disinhibit somatostatin release; the consequent activation of sst(5) receptors would potentiate the function of NMDA receptors coexisting with sst(5) receptors on noradrenergic neurons.
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PMID:Potentiation of NMDA receptor function through somatostatin release: a possible mechanism for the cognition-enhancing activity of GABA(B) receptor antagonists. 1152 21

Metabotropic G protein-coupled receptors have recently been recognized as targets for anesthetics and analgesics. In particular, G(q)-coupled receptors such as muscarinic M(1) receptors (M(1)R) and 5-hydroxytryptamine (5-HT) type 2A receptors have been reported to be targets for anesthetics. Much less is known, however, about the effects of anesthetics on G(i)-coupled receptors. Here we report a method to analyze functions of G(i)-coupled receptors in Xenopus oocytes expressing a chimeric G alpha protein. A chimeric G alpha(q) protein G alpha(qi5), which contains carboxy-terminus five amino acids of G alpha(i), enables G(i)-coupled receptors to couple to Gq-coupled receptor-mediated downstream pathways such as activation of phospholipase C. We determined acetylcholine (ACh)-induced Ca(2+)-activated Cl(-) currents in Xenopus oocytes coexpressing G(i)-coupled muscarinic M(2)receptors (M(2)R) with the chimeric G alpha(qi5). Although ACh did not induce any currents in oocytes expressing M(2)R alone, it caused robust Cl(-) currents in oocytes coexpressing M(2)R with G alpha(qi5). The EC(50) of the ACh-induced Cl(-) current mediated through G alpha(qi5) was 0.2 micromol/l, which was 2.2 times higher than that of the ACh-induced G protein-activated inwardly rectifying K(+) currents activated by G beta gamma subunits liberated from endogenously expressed G alpha(i) in Xenopus oocytes. Other G(i)-coupled somatostatin type 2, 5-HT(1A) and delta-opioid receptors, when coexpressed with G alpha(qi5) in oocytes, also caused robust Ca(2+)-activated Cl(-) currents. In oocytes coexpressing M(2)R and G alpha(qi5), a volatile anesthetic halothane inhibited M(2)R-induced Cl(-) currents in a concentration-dependent manner with the IC(50) of 1.1 mmol/l, suggesting that halothane inhibits M(2)R-induced cellular responses at clinically relevant concentrations. Treatment with the protein kinase C inhibitor GF109203X produced a 3.5-fold enhancement of the initial Cl(-) currents induced by 1 micromol/l ACh in oocytes expressing M(2)R and G(qi5). The rate of halothane-induced inhibition of Cl(-) currents elicited by ACh, however, was not changed in such oocytes pretreated with GF109203X. These findings suggest that halothane inhibits the M(2)R-induced signaling by acting at sites other than PKC activity. Collectively these findings suggest that the use of oocyte expressing G alpha(qi5) would be helpful to examine the effects of anesthetics or analgesics on the function of G(i)-coupled receptors in the Xenopus oocyte expression system.
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PMID:Analysis of the effects of halothane on Gi-coupled muscarinic M2 receptor signaling in Xenopus oocytes using a chimeric G alpha protein. 1545 70

Somatostatin receptors and glutamate N-methyl-D-aspartate (NMDA) receptors coexist on hippocampal noradrenergic axon terminals. Activation of somatostatin receptors was previously found to positively influence the function of NMDA receptors regulating norepinephrine release. The somatostatin receptors involved were pharmacologically characterized as sst5 type in experiments in Mg2+-free solutions. Here, we first confirm the pharmacology of these receptors using selective sst5 ligands in Mg2+-containing solutions. Moreover, we show by Western blot that the sst5 protein exists on purified hippocampal synaptosomal membranes. We then investigated the pathways connecting the two receptors using as a functional response the release of norepinephrine from rat hippocampal synaptosomes in superfusion. The release of norepinephrine evoked by somatostatin-14 plus NMDA/glycine was partly prevented by the protein kinase C inhibitor GF109203X [dihydrochloride3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione] and by the nonreceptor tyrosine kinase (Src) inhibitors PP2 [3-(4-chlorophenyl)1-(1,1-dimethylethyl)-1H-pyrazolo[3,4-D]pyrimidin-4-amine] and lavendustin A; it was largely and almost totally abolished by the phospholipase C inhibitor U73122 [1-(6-[([17beta]-3-methoxyextra-1,3,5[10]-trien-17-yl)amino]hexyl)-1H-pyrrole-2,5-dione] and by the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 [N-(2-[N-[4-chlorocinnamyl]-N-methyl-amino-methyl]phenyl)-N-(2-hydroxyethyl)-4-methoxy-benzene-sulfonamide-phosphate salt], respectively; and it was unaffected by the protein kinase A inhibitor H89 [N-(2-[p-bromocinnamylamino]ethyl)5-isoquinolinesulfonamide hydrochloride]. The norepinephrine release evoked by somatostatin-14/NMDA/glycine was inhibited when anti-phosphotyrosine antibodies had been entrapped into synaptosomes. Entrapping the recombinant activated tyrosine kinase pp60(c-Src) strongly potentiated the release of norepinephrine elicited by NMDA/glycine in Mg2+-free medium but failed to permit NMDA receptor activation in presence of external Mg2+ ions. The results suggest the involvement of CaMKII in the sst5 receptor-mediated activation of NMDA receptors in presence of Mg2+ and of the PLC/PKC/Src pathway in the up-regulation of the ongoing NMDA receptor activity.
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PMID:Somatostatin-induced activation and up-regulation of N-methyl-D-aspartate receptor function: mediation through calmodulin-dependent protein kinase II, phospholipase C, protein kinase C, and tyrosine kinase in hippocampal noradrenergic nerve endings. 1560 72


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