Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adrenomedullary content of neurotensin and substance P was examined 1, 6, and 12 days after hypoglycemic shock. The neurotensin content was increased 60-fold within 24 h and remained elevated for up to 12 days, whereas the substance P content was increased approximately sevenfold within 24 h of insulin treatment and returned to control levels by 12 days poststimulation. Because protein kinase A, protein kinase C, and calcium influx in the rat adrenal medulla are all stimulated following splanchnic nerve stimulation, the differential regulation of neurotensin and substance P biosynthesis following stimulation of these three pathways was examined in bovine chromaffin cells in vitro. Neurotensin levels were up-regulated by elevated potassium, forskolin, and phorbol ester in bovine chromaffin cells. Substance P levels were up-regulated by elevated potassium and forskolin but not by phorbol ester treatment. When chromaffin cells were treated with phorbol ester in combination with forskolin, neurotensin levels were increased in a synergistic fashion, whereas phorbol ester antagonized the forskolin-induced elevation of substance P levels. Earlier, it was reported that galanin biosynthesis, like neurotensin biosynthesis, is upregulated by depolarization, phorbol ester stimulation, and forskolin treatment in chromaffin cells in vitro. Here we report that galanin is also, like neurotensin, increased greater than 60-fold after stimulation of the rat adrenal medulla in vivo. Neuropeptide-specific combinatorial effects of stimulating the calcium, protein kinase A, and protein kinase C signaling pathways may underlie the quantitative differences between galanin and neurotensin compared with substance P up-regulation in rat adrenal medulla after splanchnic nerve stimulation in vivo.
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PMID:Transsynaptic regulation of galanin, neurotensin, and substance P in the adrenal medulla: combinatorial control by second-messenger signaling pathways. 137 91

Neurotensin (NT), a hypothalamic peptide which is also contained in the chromaffin granules of adrenal medullary cells, did not affect either basal or ACTH-stimulated secretory activity of isolated rat zona glomerulosa (ZG) cells. Conversely, NT was found to exert a strong dose-dependent inhibitory effect on aldosterone response of ZG cells to their two main calcium-dependent secretagogues angiotensin-II and potassium. These findings suggest that NT may interfere with the angiotensin-II- or potassium-induced activation of protein kinase C, possibly by blunting the rise in the cytosolic calcium concentration.
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PMID:Neurotensin inhibits the stimulatory effect of angiotensin-II and potassium on aldosterone secretion by rat zona glomerulosa cells. 165 Jul 5

Neurotensin receptors have been shown previously to be coupled to polyphosphoinositide turnover and intracellular Ca2+ ([Ca2+]i) mobilization in HT-29 colonic epithelial cells (Bozou et al. Biochem. J. 264: 871, 1989; Turner et al. J. Pharmacol. Exp. Ther. 253: 1049, 1990). In this study, neurotensin was found to enhance dramatically the Ba2(+)- and tetraethylammonium chloride-sensitive K(+)-efflux rate (measured with 86Rb+) in the presence of ouabain and bumetanide, with basal efflux increasing 4.5 +/- 0.5-fold with 10 nM neurotensin. The K(+)-efflux rate, which was partially dependent on the extracellular Ca2+ concentration, was also increased by carbachol and ATP, two other [Ca2+]i-mobilizing agonists in HT-29 cells, as well as by the Ca2+ ionophores ionomycin and A23187, suggesting that the efflux was through Ca2(+)-activated K+ channels. Pretreatment of cells with neurotensin, carbachol, or ATP desensitized subsequent neurotensin-stimulated efflux by 82, 57, and 63%, respectively, confirming our previous results which indicated homologous and heterologous desensitization of the neurotensin receptor-signal transduction pathway. Pretreatment of cells with the protein kinase C activators phorbol 12-myristate 13-acetate (PMA) and mezerein did not affect [Ca2+]i mobilization or K+ efflux directly but desensitized neurotensin-stimulated efflux by greater than 80%. Pretreatment (2 h) with PMA also decreased K+ efflux in response to ionomycin by 59%, although ionomycin-induced [Ca2+]i mobilization was not inhibited. Downregulation of protein kinase C by overnight pretreatment with PMA resulted in recovery of ionomycin-stimulated efflux. These results suggest that agonist-stimulated Ca2(+)-activated K+ channels in HT-29 cells are regulated at multiple steps in the signal transduction pathway.
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PMID:Regulation of calcium-activated potassium efflux by neurotensin and other agents in HT-29 cells. 198 79

It has previously been shown that neurotensin binds to high-affinity receptors in the adenocarcinoma HT29 cell line, and that receptor occupancy leads to inositol phosphate formation. The present study was designed to investigate further the effects of neurotensin on calcium mobilization and protein kinase C (PKC) activation in HT29 cells, and to assess the role of GTP-binding proteins (G-proteins) in the neurotensin response. Direct measurements of cytosolic Ca2+ variations using the fluorescent indicator quin 2 showed that neurotensin (0.1-1 microM) elicited Ca2+ transients in HT29 cells. These transients occurred after the neurotensin-stimulated formation of Ins(1,4,5)P3, as measured by means of a specific radioreceptor assay. In addition, the peptide induced a decrease in the 45Ca2+ content of cells previously equilibrated with this isotope. The peptide effect was rapid, long-lasting and concentration-dependent, with an EC50 of 2 nM. Phorbol 12-myristate 13-acetate (PMA) inhibited by 50% the neurotensin effects on both intracellular Ca2+ and inositol phosphate levels. The inhibition by PMA was abolished in PKC-depleted cells. Pertussis toxin had no effect on either the Ca2+ or inositol phosphate responses to neurotensin. Epidermal growth factor (EGF) receptors which are present in HT29 cells have been shown to be down-regulated through phosphorylation by PKC in a variety of systems. Here, PMA markedly (70-80%) inhibited EGF binding to HT29 cells. Scatchard analysis revealed that PMA abolished the high-affinity component of EGF binding, an effect that was totally reversed in PKC-depleted cells. In contrast, neurotensin slightly (10-20%) inhibited EGF binding to HT29 cells, and its effect was only partly reversed by PKC depletion. Neurotensin had no detectable effect on sn-1,2-diacylglycerol levels in HT29 cells, as measured by a specific and sensitive enzymic assay. In membranes prepared from HT29 cells, monoiodo[125I-Tyr3]neurotensin bound to a single population of receptors with a dissociation constant of 0.27 nM. Sodium and GTP inhibited neurotensin binding in a concentration-dependent manner. Maximal inhibition reached 80% with Na+ and 35% with GTP.IC50 values were 20 mM and 0.2 microM for Na+ and GTP respectively. Li+ and K+ were less effective than Na+ and the effects of GTP were shared by GDP and guanosine-5'-[beta gamma- imido]triphosphate but not by ATP. Scatchard analysis of binding data indicated that Na+ and GTP converted the high-affinity neurotensin-binding sites into lower affinity binding sites. The properties of the effects of Na+ and GTP on neurotensin-receptor interactions are characteristic of those receptors which interact with G-proteins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neurotensin stimulates inositol trisphosphate-mediated calcium mobilization but not protein kinase C activation in HT29 cells. Involvement of a G-protein. 255 20

Neurotensin, bradykinin and somatostatin inhibited in a time- and concentration-dependent manner prostaglandin E1- or forskolin-stimulated cAMP production in neuroblastoma N1E115 cells. Cell treatment with 1 microgram/ml pertussis toxin for 6 hours reversed the inhibition elicited by peptides after short incubation periods (less than or equal to 1 min) but, in contrast, had no effect after longer incubation periods (greater than or equal to 3 min). Fluoroaluminate also inhibited prostaglandin E1-stimulated cAMP production in N1E115 cells, and this effect was not reversed by pertussis toxin. The 6 hour treatment with pertussis toxin was shown to be sufficient to ADP ribosylate virtually all of the 41 kD protein substrate corresponding to the alpha subunit of Gi. Protein kinase C activation with phorbol ester did not inhibit basal or stimulated cAMP production. Our data point to the existence of both pertussis toxin sensitive and insensitive mechanisms of neuropeptide-mediated inhibition of cAMP formation in N1E115 cells. The toxin insensitive response is not mediated by protein kinase C. The possibility is discussed that it results from the activation of a pertussis toxin insensitive G protein.
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PMID:Neurotensin, bradykinin and somatostatin inhibit cAMP production in neuroblastoma N1E115 cells via both pertussis toxin sensitive and insensitive mechanisms. 256 13

Whole-cell patch-clamp recordings were used to investigate electrophysiological effects of neurotensin on acutely isolated dopaminergic (DA) neurons of the rat substantia nigra pars compacta (SNC). During current-clamp recordings, neurotensin depolarized DA neurons and triggered action potentials. Under voltage-clamp recordings, neurotensin evoked an inward current at a holding potential of -50 mV. Neurotensin-induced inward currents reversed the direction at -5 mV and became smaller as the membrane potential was hyperpolarized from -75 mV. With potassium-free recording solutions, neurotensin evoked voltage-insensitive cationic currents. With sodium-free external solution, neurotensin also caused inward currents by reducing the inwardly rectifying potassium conductance. Neurotensin-induced inward currents mainly resulted from an increase in a non-selective cationic conductance. Neurotensin-evoked cationic currents were inhibited by the intracellular perfusion of 1 mM guanosine-5'-O-(2-thiodiphosphate). In DA neurons internally perfused with 0.5 mM guanosine-5'-O-(3-thiotriphosphate), the cationic current produced by neurotensin became irreversible. Pretreating DA neurons with 500 ng/ml pertussis toxin (PTX) did not significantly affect the ability of neurotensin to evoke cationic currents. Internal perfusion of heparin (2 mg/ml), an inositol 1,4,5-trisphosphate (IP3) receptor antagonist, and buffering intracellular calcium with the Ca(2+)-chelator BAPTA (10 mM) suppressed neurotensin-induced cationic currents. Dialyzing DA neurons with protein kinase C (PKC) inhibitors, staurosporine and PKC(19-31), failed to prevent neurotensin from evoking cationic currents. It is concluded that PTX-insensitive G-proteins mediate neurotensin-induced enhancement of the cationic conductance of SNC DA neurons.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Neurotensin increases the cationic conductance of rat substantia nigra dopaminergic neurons through the inositol 1,4,5-trisphosphate-calcium pathway. 755 60

Whole-cell voltage-clamp recordings were used to investigate the molecular transduction mechanism by which neurotensin decreases the inwardly rectifying potassium conductance of dopaminergic (DA) neurons acutely isolated from the rat substantia nigra (SN). With sodium-free external solution, neurotensin evoked inward currents by reducing the inwardly rectifying K+ conductance. Neurotensin inhibition of the K+ current was blocked by the internal perfusion of 1 mM GDP-beta-S. When DA neurons were internally perfused with 0.5 mM GTP-gamma-S, the reduction of K+ conductance produced by neurotensin became irreversible. Neurotensin still inhibited K+ currents in DA neurons pretreated with 500 ng/ml pertussis toxin (PTX). Dialyzing DA neurons with protein kinase C (PKC) inhibitors, staurosporine and PKC(19-31), prevented neurotensin from decreasing the potassium conductance. Our results propose that neurotensin activates PKC of SN DA neurons via PTX-insensitive G-proteins and that PKC mediates the neurotensin inhibition of inwardly rectifying potassium currents.
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PMID:Protein kinase C mediates neurotensin inhibition of inwardly rectifying potassium currents in rat substantia nigra dopaminergic neurons. 772 45

Effects of various secretagogues on secretion of neurotensin from a pancreatic islet cell carcinoma cell line (QGP-1N) were examined. Carbachol stimulated secretion of neurotensin concentration-dependently in the range of 10(-6) - 10(-4) M. The neurotensin secretion stimulated with 10(-5) M carbachol was completely inhibited by atropine at 10(-5) M. Phorbol ester and calcium ionophore (A23187) stimulated secretion of neurotensin. The removal of extracellular Ca2+ suppressed the secretion through the stimulation with 10(-5) M carbachol. Fluoride, an activator of guanine nucleotide-binding (G) protein, stimulated secretion of neurotensin. Neurotensin released into culture medium through stimulation with carbachol coeluted with neurotensin 1-13 on a gel-chromatography. Our results suggest that secretion of neurotensin from QGP-1N cells is mainly regulated by acetylcholine through muscarinic receptors coupled to G protein and that an increase in intracellular Ca2+ and protein kinase C play an important role in stimulus-secretion coupling.
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PMID:Secretion of neurotensin from a human pancreatic islet cell carcinoma cell line (QGP-1N). 813 14

Neurotensin (NT) is a neuropeptide that is important in a variety of biological processes such as signal transduction and cell growth. NT effects are mediated by a single class of cell-surface receptors, known as neurotensin receptors (NTRs), which exhibit structural features of the G-protein-coupled receptors superfamily. We investigated NTR signalling properties with Chinese hamster ovary (CHO) cells stably transformed with human NTR (hNTR). First, we showed that NTR stimulation by NT induced the activation of the mitogen-activated protein kinases (MAPKs) in time- and dose-dependent manners. Both p42 and p44 MAPK isoforms were retarded in gel-shift assays, which was consistent with their activation by phosphorylation. In addition we showed that NT caused a prolonged activation of MAPK as measured by in-gel kinase assay. Secondly, we demonstrated that NT induced the expression of the growth-related gene Krox-24 at the protein level, as assessed by Western-blot analysis, and at the transcriptional level, as demonstrated in CHO cells transfected with hNTR and a reporter gene for Krox-24. Activation of MAPK and induction of Krox-24 were both prevented by the NTR antagonist SR 48692, confirming the specific action on NTR. Furthermore we observed coupling of NTR to a mitogenic pathway and Krox-24 induction in the human adenocarcinoma cell line HT29, which naturally expresses NTRs. Considering coupling pathways between NTR stimulation and MAPK activation, we observed a partial inhibition by pertussis toxin (PTX) and a complete blockade by the protein kinase C (PKC) inhibitor GF 109203X. Taken together, these results suggest that (1) stimulation of NTR activates the MAPK pathway by mechanisms involving dual coupling to both PTX-sensitive and PTX-insensitive G-proteins as well as PKC activation, and (2) these effects are associated with the induction of Krox-24, which might be a target of MAPK effector.
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PMID:Activation of mitogen-activated protein kinase couples neurotensin receptor stimulation to induction of the primary response gene Krox-24. 894 79

The mouse intestinal neuroendocrine tumor cell line STC-1 secretes cholecystokinin (CCK) and other hormones. We investigated the role of Ca2+, calmodulin (CaM), and protein kinase C (PKC) in the regulation of CCK release from STC-1 cells. Phorbol 12-myristate 13-acetate (TPA) significantly stimulated CCK release. Staurosporine significantly inhibited CCK release from STC-1 cells stimulated by TPA in a dose-dependent manner. The absence of extracellular calcium completely inhibited CCK release from TPA-stimulated STC-1 cells. Neurotensin did not stimulate CCK release from these cells. W-7, a CaM antagonist, reduced CCK release from STC-1 cells stimulated by bombesin in a dose-dependent manner. These findings suggest that CaM and PKC play an important role in the regulation of CCK release from STC-1 cells stimulated by bombesin.
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PMID:Involvement of calmodulin and protein kinase C in cholecystokinin release by bombesin from STC-1 cells. 1103 66


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