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

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

Phorbol myristate acetate (PMA) stimulates pituitary hormone release by activating protein kinase C (PKC). By doing so, PMA mimics the diacylglycerol (DAG) produced by the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2). The present study demonstrates that PMA and DAG augment prolactin release and attenuate the elevations of inositol phosphates (IPX) elicited by thyrotropin-releasing hormone (TRH), angiotensin II, neurotensin, bombesin and gonadotropin-releasing hormone (GnRH) in normal anterior pituitary and prolactin-secreting 7315a tumor cells. 4 alpha-Phorbol 12,13-didecanoate (PDD), an inactive analog of PMA, was found to have no effect on IPX levels; the PKC inhibitor H-7 attenuated the PMA-related inhibition of TRH-induced IPX. To examine whether PMA attenuates IPX generation or increases IPX metabolism, the effects of PMA on the levels of inositol phosphates and phosphoinositides were determined. TRH increased inositol trisphosphate, inositol bisphosphate and inositol monophosphate, and decreased PIP2 and phosphatidylinositol 4-phosphate levels. PMA had no effect on basal phosphoinositide or inositol phosphate levels, but attenuated the effects of TRH on these parameters. Thus PMA and DAG, by a mechanism involving PKC-mediated attenuation of secretagogue-induced hydrolysis of PIP2, decreases IPX production, and therefore PKC activation may exert negative feedback regulation on anterior pituitary secretory activity.
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PMID:Attenuation of pituitary polyphosphoinositide metabolism by protein kinase C activation. 282 75

In this work, we tested the effect of ion channel blockers and of phorbol ester treatments on [3H]dopamine ([3H]DA) release and neurotensin (NT)-induced facilitation of [3H]DA release from cultures of rat fetal mesencephalic cells. The potassium channel blockers tetraethylammonium and 4-aminopyridine increased basal [3H]DA release and decreased K(+)-evoked [3H]DA release, whereas apamin was without effect. K(+)-evoked [3H]DA release was decreased by omega-conotoxin and nifedipine, totally suppressed by cadmium, and unaffected by amiloride. These results show the differential sensitivity of [3H]DA release to blockade of various ion channels and suggest the involvement of N-type, L-type, and non-L-non-N-type, but not T-type, voltage-sensitive calcium channels in K(+)-evoked release. Phorbol 12-myristate 13-acetate increased both spontaneous and K(+)-evoked [3H]DA release, suggesting a modulatory action of protein kinase C on DA release in this system. Unexpectedly, however, the effects of the phorbol ester were not counteracted by the protein kinase C inhibitors H7, staurosporine, or polymyxin B. NT-induced facilitation of K(+)-evoked [3H]DA release was insensitive to most of the ion channel blockers, except cadmium (64% decrease in NT effect), suggesting that the corresponding potassium and calcium channels were not involved in the effect of NT on [3H]DA release in this system. The NT effect was totally suppressed by phorbol ester treatments, indicating a possible desensitization of the corresponding transduction mechanisms after protein kinase C activation.
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PMID:Effects of ion channel blockers and phorbol ester treatments on [3H]dopamine release and neurotensin facilitation of [3H]dopamine release from rat mesencephalic cells in primary culture. 751 Jul 81

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

Brief phorbol ester treatment of BON cells results in a persistent release and cellular depletion of immunoreactive chromogranin A (CGA-IR) and neurotensin (NT-IR) cell contents. The purpose of the present study was to characterize the effects of 12-O-tetradecanoyl phorbol-13-acetate (TPA) on the secretion, biosynthesis, and steady-state messenger RNA (mRNA) levels of chromogranin A (CGA) and of a coresident peptide, neurotensin, by a novel human pancreatic carcinoid cell line, called BON. Acute TPA treatment (100 nM, 1 h) of BON cells resulted in 20- and 40-fold elevations in release of CGA-IR and NT-IR, respectively; and a 70-90% depletion of CGA-IR and NT-IR cell contents. TPA treatment also increased the biosynthetic rate of CGA-IR. Steady-state mRNA levels of CGA and NT/N (neurotensin/neuromedin N) were unchanged. Cell contents of CGA-IR and NT-IR were not replenished for a period of up to 6 days; secretion of CGA-IR and NT-IR persisted. In addition, BON cells failed to release CGA in response to stimulation by ionomycin and A23187 several days after acute TPA treatment. Our data indicate that the lack of replenishment of cell contents of CGA-IR and NT-IR is not due to decreases in steady-state CGA-IR and NT-IR mRNA levels, nor is it due to a decrease in biosynthesis of CGA-IR, but it is the result of a loss in the ability of TPA-treated BON cells to store and secrete CGA-IR and NT-IR in a regulated manner. These effects of TPA are mediated through the PKC pathway.
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PMID:Phorbol ester-induced alteration in the pattern of secretion and storage of chromogranin A and neurotensin in a human pancreatic carcinoid cell line. 772 Jun 75

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

The neuronal growth-associated protein B-50/GAP-43 is a substrate for protein kinase C, binds to calmodulin in a calcium-independent manner, and in vitro is subject to an endogenous and chymotrypsin-mediated hydrolysis in the vicinity of the single kinase C phosphorylation site. All of these processes can be influenced by corticotrophin (ACTH). In the present study we have investigated whether these biochemical interactions involving B-50 could have common structural determinants. Chymotryptic digestion of B-50 in the presence or absence of a nonionic detergent and ACTH demonstrated that hydrolysis is potentiated by a lipid-like environment that primarily affects the protein rather than the protease or the peptide. Furthermore, this lipid dependency appears to extend to the binding of dephosphorylated B-50 to calmodulin, which appears to occur only in the presence of a nonionic detergent or lipid and the absence of calcium. A structure-activity study for ACTH-mediated inhibition of B-50 proteolysis by an endogenous protease that copurifies with B-50 in a detergent extract of synaptosomal plasma membranes showed that ACTH1-24, ACTH5-24, ACTH5-16, dynorphin, and corticostatin inhibited the conversion of rat B-50 to B-5041-226. In contrast, ACTH7-16, Org2766, and neurotensin had no detectable effect on B-50 proteolysis at concentrations of 10 and 50 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Detergents and peptides alter proteolysis and calmodulin binding of B-50/GAP-43 in vitro. 793 2

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

This study has examined the involvement of the Ca(2+)-signalling pathway in the regulation of agonist-stimulated cAMP responses in the human colonic adenocarcinoma cell line, HT29-cl.19A. The muscarinic agonist, carbachol (CCh) stimualted rapid increases in cellular IP3 and cytosolic Ca2+, [Ca2+]i in HT29-cl.19A cells. These were accompanied by a small but significant increase in basal cAMP levels and a marked (3-4-fold) potentiation of both forskolin- (FSK) and VIP-stimulated cAMP generation. Similar effects were observed with two other Ca(2+)-mobilising agonists, neurotensin and ATP. The failure of CCh to elicit potentiation of adenylate cyclase in broken cell preparations indicated an indirect action. Potentiation could be mimicked by the calcium ionophore, ionomycin, and thapsigargin and inhibited 70-90% by depleting intracellular Ca2+ stores suggesting that a rise in [Ca2+]i is the primary mediator of this response. In contrast, increasing [Ca2+]i levels to > 500 nM caused a significant inhibition of FSK-stimulated cAMP generation. The involvement of protein kinase C (PKC) was also assessed. PKC activators phorbol 12,13 dibutyrate (PDB) and 1-oleoyl-2-acetyl glycerol (OAG) potentiated FSK-stimulated cAMP production by 50-70% though PDB markedly inhibited the cAMP response to the receptor-mediated cAMP agonist, VIP. Neither effect could be elicited by the inactive phorbol ester, 4 alpha-phorbol, 12,13 didecanoate (PDD). PKC inhibitors staurosporine and H7 reduced by approximately 25% the CCh-induced potentiation of FSK-stimulated cAMP generation. In conclusion, these results suggest that stimulation of the phosphoinositidase C pathway in HT29-cl.19A colonocytes induces a 'sensitisation' of the adenylate cyclase system resulting in a dramatic amplification of agonist-stimulated cAMP generation. Increases in [Ca2+]i appear to be an important mediator of potentiation though activation of PKC may also play a significant role.
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PMID:Ca(2+)-mobilising agonists potentiate forskolin- and VIP-stimulated cAMP production in human colonic cell line, HT29-cl.19A: role of [Ca2+]i and protein kinase C. 814 16

Aromatase in the diencephalic neurons, the level of which increases transiently during the prenatal to neonatal period, has been suggested to be involved in control of sexual behavior and differentiation of the CNS. Effects of neurotransmitters on levels of aromatase mRNA in cultured neurons were investigated to determine factors regulating the developmental increase that occurs in level of fetal brain aromatase. The expression of aromatase in diencephalic neurons of fetal mice at embryonic day 13, cultured in vitro, was significantly affected by alpha 1-adrenergic receptor ligands. Aromatase mRNA levels were higher in neurons treated with the alpha 1-agonist phenylephrine than in control neurons, whereas prazosin, an alpha 1-antagonist, suppressed this increase, and ligands for alpha 2- or beta-adrenergic receptors did not exert any influence. The profile of alpha 1-adrenergic receptor subtypes during actual development in vivo suggested that the alpha 1B subtype is in fact responsible for the signal transduction. Substance P, cholecystokinin, neurotensin, and brain natriuretic peptide also increased the level of expression along with phorbol 12-myristate 13-acetate and dibutyrylcyclic GMP, whereas forskolin and dibutyryl-cyclic AMP caused a decrease. These data indicate that stimulation via alpha 1 (possibly alpha 1B)-adrenergic receptors, as well as receptors of specific neuropeptides, controls the expression of aromatase in embryonic day 13 diencephalic neurons through activation of protein kinase C or G. beta-Adrenergic receptors would not appear to participate in the regulation, judging from their developmental profile, although cyclic AMP might be a suppressive second messenger.
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PMID:Neurotransmitter-mediated regulation of brain aromatase: protein kinase C- and G-dependent induction. 886 18


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