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)

Previous studies using phorbol esters and cell-free preparations suggest that protein kinase C (PKC) may regulate Cl- secretion and apical membrane Cl- channels in airway epithelium. To determine whether PKC may be involved in receptor-mediated control of secretion, we measured the mass of diacylglycerol (DAG) generated by two Cl- secretagogues, isoproterenol and bradykinin. Bradykinin increased cellular DAG at concentrations similar to those that increase inositol phosphates, suggesting that bradykinin stimulates phosphatidylinositol hydrolysis, as observed in other systems. Isoproterenol also increased cellular DAG at concentrations similar to those that stimulate adenosine 3',5'-cyclic monophosphate (cAMP) accumulation. The beta-adrenergic receptor antagonist, nadolol, blocked and cell-permanent analogues of cAMP mimicked the effect of isoproterenol. However, isoproterenol does not stimulate phosphatidylinositol turnover. Simultaneous addition of maximal concentrations of isoproterenol and bradykinin produced additive increases in DAG. To test the possibility that the isoproterenol-induced increase in DAG came from phosphatidylcholine turnover, we measured the release of water-soluble choline metabolites and the incorporation of choline into cellular lipids. Although phorbol ester and bradykinin stimulated phosphatidylcholine turnover, isoproterenol did not. These results suggest that isoproterenol and bradykinin generate DAG from the following different lipid sources: bradykinin stimulates phosphatidylinositol hydrolysis to produce DAG; isoproterenol stimulates an increase in DAG from unknown sources. The data suggest that simultaneous activation of cAMP-dependent protein kinase and PKC may occur during receptor-mediated stimulation of Cl- secretion.
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PMID:Isoproterenol, cAMP, and bradykinin stimulate diacylglycerol production in airway epithelium. 216 9

The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA), a selective activator of protein kinase C, had no effect on the sensitivity to Ca2+ or verapamil of K+-depolarized taenia preparations from the guinea-pig caecum, despite the use of high concentrations (1 microM for 3 h); this preparation is sensitive to Ca2+ channel activators and antagonists. TPA (0.03-3 microM) caused a slow contraction of rat aorta preparations; the contractions were resistant to the calcium-antagonists nifedipine (0.01 microM), verapamil (10 microM), diltiazem (10 microM) and cinnarizine (10 microM), but were antagonized by N-(6-aminohexyl)-5-chloro-1-naphthalensulphonamide (W-7, 50-200 microM). Prolonged exposure to TPA (greater than 2 h) resulted in spontaneous contractions which were sensitive to verapamil (1 microM). Isoprenaline and sodium nitroprusside relaxed phenylephrine-induced contractions in rat aorta preparations. TPA (0.3 microM) blocked the maximal response to isoprenaline but not to sodium nitroprusside indicating that TPA did selectively activate protein kinase C under these experimental conditions. These findings indicate that protein kinase C activation does not result in direct effects on Ca2+ channel function, but may exert effects indirectly (e.g. by modifying intracellular sensitivity to Ca2+, Ca2+ extrusion, or cellular depolarization).
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PMID:Interaction of phorbol esters with Ca2+ channels in smooth muscle. 244 May 6

The molecular mechanisms of myelin formation/reformation in the central nervous system are unknown. In previous work we have demonstrated that mature oligodendrocytes (OLG) respond to a signal(s), elicited by their adhesion to a substratum, by turning on a myelinogenic metabolism. Events occurring within 24 hr of adhesion include generation of diacylglycerol, activation of protein kinase C, phosphorylation of myelin basic protein, and enhanced synthesis of myelin lipids and proteins. To elucidate the mechanism(s) of signal transduction, we have investigated whether OLG-substratum interaction influences the level of basal cAMP and the expression of receptors coupled to adenylate cyclase. By using ovine brain OLG we have found that adhesion to a polylysine-coated surface for 24 hr increased the basal level of cAMP 2-fold and altered the expression (assessed by cAMP production) of receptors coupled to adenylate cyclase. Isoproterenol (beta-adrenergic agonist) augmented cAMP from 4 to 26 pmol/mg of protein in adhering OLG but had no such effect in nonattached OLG. Adhesion of OLG was accompanied by rapid synthesis of ethanolamine plasmalogen, a class of lipids believed to be associated with beta-adrenergic receptors. Nonattached OLG responded to prostaglandin E1 with only a 3-fold stimulation in their cAMP content; in attached OLG, 6-fold stimulation was observed. In contrast, vasoactive intestinal polypeptide elicited a 3-fold increase in cAMP in nonattached OLG but, following 24 hr of attachment, OLG did not respond to vasoactive intestinal polypeptide. The increase of cellular cAMP levels was accompanied by a 2.5-fold gain in protein kinase A. OLG-substratum adhesion resulted also in phosphorylation of the OLG/myelin protein, 2',3'-cyclic nucleotide 2'-phosphodiesterase, which proved to be a substrate for cAMP and phospholipid-, Ca2+-dependent protein kinases. These findings, in conjunction with our earlier work, implicate cAMP and diacylglycerol in signaling myelinogenesis; they suggest that phosphorylation/dephosphorylation of myelin basic protein and 2',3'-cyclic nucleotide 2'-phosphodiesterase may be key processes in the cascade of events that are initiated by adhesion of OLG to a polylysine surface (possibly acting as a surrogate for axons) and culminate in the reformation of myelin.
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PMID:Oligodendrocyte substratum adhesion modulates expression of adenylate cyclase-linked receptors. 244 85

It has been suggested that protein kinase C activation may have a role in the maintained, 'latch-bridge' phase of smooth muscle contraction. We have examined the effects of a range of smooth muscle relaxants on the maintained contraction produced in the guinea-pig parenchymal lung strip by the protein kinase C activator, 4 beta-phorbol dibutyrate (4 beta-PDBu). The maximum histamine contraction (produced by 10 microM) was used as a standard and the effects of the smooth muscle relaxants were also studied on this histamine-induced contraction. After 4 beta-PDBu, 1 microM, had produced contraction, enprofylline, forskolin and papaverine caused concentration-dependent relaxation, producing total reversal of the contraction, while prostaglandin E2 and prostacyclin caused a concentration-dependent relaxation but less than total reversal. The concentrations required for the effects on the phorbol ester contraction were 10 to 100-fold higher than were necessary for relaxation of the maximum contraction produced by histamine. Isoprenaline, 1 microM, a concentration which caused total reversal of the histamine-induced contraction, caused only 22% decrease of the phorbol dibutyrate-induced contraction and no further relaxation occurred with higher concentrations. Cromakalim--a potassium channel activator proposed as a therapy for nocturnal asthma--had virtually no effect on preparations pre-contracted with 4 beta-PDBu, 1 microM, or histamine, 10 microM, but caused about 70% and 20% reversal of the contraction produced by 3 microM histamine and 100 nM 4 beta-PDBu respectively. When single doses of the relaxants were administered before a series of doses of 4 beta-PDBu given cumulatively, enprofylline, 1 microM, and aminophylline, 100 microM and 1 microM, caused a moderate right-shift of the phorbol dibutyrate concentration-response curve, but isoprenaline, 1 microM, was less effective, while cromakalim had no discernible effect. These results are discussed in the light of suggestions that inappropriate activation of protein kinase C in smooth muscle cells, may contribute to the pathogenesis of the late phase of asthma.
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PMID:The effect of smooth muscle relaxants working through different transduction mechanisms on the phorbol dibutyrate-induced contraction of the guinea-pig lung parenchymal strip: possible relevance for asthma. 248 2

The secretion of parathyroid hormone (PTH) is inversely related to the extracellular Ca2+ concentration (Ca2e+). To test the hypothesis that a Ca2+ sensor on the surface of parathyroid cells is involved in Ca2+-regulated PTH secretion, limited trypsinization of bovine parathyroid cells was carried out. Treatment with trypsin (1.1-10 mg/ml) inhibited, in a dose-dependent manner, PTH secretion stimulated by lowering Ca2e+ from 2.0 to 0.5 mmol/l. In control cells, activation of protein kinase C with 12-O-tetradecanoylphorbol-13-acetate (TPA) enhanced PTH secretion at 2.0 mmol Ca2e+/l but not at 0.5 mmol Ca2e+/l. In trypsinized cells, however, TPA enhanced PTH secretion at both 0.5 and 2.0 mmol Ca2e+/l. Isoproterenol-stimulated PTH secretion was maintained in trypsinized cells, but reduced cyclic AMP production revealed that some beta-adrenergic receptors were destroyed. The cytosolic free Ca2+ concentration (Ca2i+), as measured with fura-2, was raised within seconds in response to increasing Ca2e+ from 0.5 to 2.0 mmol/l and was then lowered within 1 min to a sustained plateau; the changes were the same in trypsinized and control cells. In conclusion, trypsinization of parathyroid cells abolished Ca2+-regulated PTH secretion without affecting Ca2i+.
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PMID:Trypsinization of bovine parathyroid cells abolishes Ca2+-regulated parathyroid hormone secretion. 254 48

Over the past few years, the importance of calcium and cyclic AMP in the regulation of vascular smooth muscle tone has been well documented. We used a primary culture of rat aortic myocytes to study the effect of protein kinase C on isoproterenol- and forskolin-stimulated cyclic AMP production. Addition of the protein kinase C activator 12-O-tetradecanoylphorbol-13-acetate (TPA) to these cells, but not an inactive analog, increased the stimulation of cyclic AMP production induced with isoproterenol or forskolin without changes in the apparent affinity of these compounds but did not affect the basal cAMP level. TPA also enhanced the cholera toxin-stimulated cyclic AMP accumulation. Isoproterenol and cholera toxin increased the forskolin apparent potency suggesting that interaction of activatory GTP-dependent protein with the catalytic subunit of adenylate cyclase facilitates forskolin interaction to the catalytic subunit. Treatment of myocytes with pertussis toxin had no effect on the basal level of cyclic AMP production and did not significantly modify isoproterenol- and forskolin-induced stimulation. Pertussis toxin treatment of cells did not affect the TPA-enhanced isoproterenol or forskolin stimulations suggesting that pertussis toxin and TPA actions would not share a common target of myocyte adenylate cyclase system. Our data would be in agreement with a possible direct interaction of protein kinase C with the catalytic subunit of adenylate cyclase system.
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PMID:Phorbol ester modulation of cyclic AMP accumulation in a primary culture of rat aortic smooth muscle cells. 283

The actions of cyclic AMP are subject to several levels of post-receptor modulation in cardiac tissue. Isoproterenol and prostaglandin E1 both stimulate cAMP accumulation, but only isoproterenol causes activation of particulate cAMP-dependent protein kinase, leading to activation of phosphorylase kinase and glycogen phosphorylase, and inhibition of glycogen synthase. Through the use of isolated, adult ventricular myocytes, we have determined that the hormone-specific activation of glycogen phosphorylase is due to subcellular compartmentation of cAMP. There is some evidence that cyclic nucleotide phosphodiesterases, whose activity is stimulated by alpha 1-adrenergic agonists in isolated myocytes, may have a role in compartmentation. Phosphoinositide hydrolysis is stimulated by alpha 1 and muscarinic agonists, presumably leading to activation of protein kinase C, which in turn has multiple effects on hormone-sensitive adenylate cyclase.
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PMID:Post-receptor modulation of the effects of cyclic AMP in isolated cardiac myocytes. 284 10

The early effects (0-120 s) of the beta-adrenergic secretagogue isoproterenol (2.10(-5) M) and the muscarinic secretagogue carbamoylcholine (2.10(-6) M) on various parameters of lipid and phospholipid metabolism were studied in isolated guinea pig parotid acinar cells. Both agonists enhanced within 10-20 s the incorporation of radioactive palmitate into the diacylglycerol, the triglyceride, and the phosphatidylinositol fractions but significantly diminished radioactive palmitate recovered in the acyl-CoA fraction. Carbamoylcholine decreased and isoproterenol increased the recovery of radioactive palmitate in the free fatty acid fraction. All changes had returned almost to control levels after 120 s. In cells prelabeled with [3H]arachidonate, carbamoylcholine exerted similar effects, whereas isoproterenol was almost ineffective. Both agonists stimulated the incorporation of radioactive glycerol into diacylglycerols 2-3-fold, while only carbamoylcholine stimulated the incorporation of [32P]phosphate into phosphatidylinositol and phosphatidate. Both agonists induced an increase in total diacylglycerols, carbamoylcholine being about twice as effective as isoproterenol. A lower concentration of carbamoylcholine (6.5.10(-7) M) had the same quantitative effect as 2.10(-5) M isoproterenol on the increase of total diacylglycerols. Even under these conditions carbamoylcholine, but not isoproterenol led to a significant translocation of protein kinase C from the soluble to the particulate fraction. Isoproterenol remained ineffective in this respect also when intracellular free calcium was increased with a calcium ionophore. This is explained by the finding that isoproterenol stimulates preferentially the formation of 2,3-sn-diacylglycerol, and carbamoylcholine preferentially stimulates the formation of 1,2-sn-diacylglycerol. The results indicate that in the guinea pig parotid acinar cell the two agonists do not only lead to activation of a triglyceride lipase (isoproterenol) or phosphoinositide-specific phospholipase(s) (carbamoylcholine), but also to a rapid change of flux through a number of other enzyme-catalyzed reactions involved in diacylglycerol turnover.
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PMID:Early effects of beta-adrenergic and muscarinic secretagogues on lipid and phospholipid metabolism in guinea pig parotid acinar cells. Stimulation of 2,3-sn-diacylglycerol formation by isoproterenol. 289 Jun 41

Infusion of a phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), known to stimulate protein kinase C, caused a gradual, sustained increase in perfusate immunoreactive atrial natriuretic peptide (IR-ANP) concentration and a more rapid increase in perfusion pressure in the isolated perfused rat heart. Administration of isoprenaline resulted in a rapid rise in IR-ANP release whereas methoxamine induced a sustained increase in IR-ANP secretion into the perfusion fluid. Methoxamine, when infused in combination with TPA, enhanced both IR-ANP secretion and the increase in perfusion pressure produced by phorbol ester. Isoprenaline also acted synergistically on TPA-induced IR-ANP release but attenuated the coronary vasoconstriction produced by phorbol ester. The TPA-induced increase in IR-ANP secretion was attenuated significantly by infusion of atenolol and slightly by infusion of prazosin, neither of which affected TPA-induced vasoconstriction. The vasoconstrictor response to infusion of phorbol ester was similar but the secretory response was attenuated in hearts from rats pretreated with reserpine. The results indicate that adrenoceptor stimulation interacts differentially with phorbol ester-induced ANP secretion and vasoconstriction in the perfused rat heart. Our results also suggest that the effect of TPA on perfusion pressure appears to be due to its direct action on vascular smooth muscle cells but that a part of the TPA effect on ANP secretion may be an indirect one.
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PMID:Adrenergic effect on the atrial natriuretic peptide secretion and vasoconstriction induced in the perfused rat heart by phorbol ester. 289 74

Tumour-promoting phorbol esters such as phorbol 12-myristate 13-acetate (PMA) have been reported to modulate beta-adrenergic receptor responses in various cell types, presumably by the activation of protein kinase C. In the present investigation we assessed the effect of PMA on the beta-adrenergic receptor-adenylate cyclase system of human mononuclear leukocytes (MNL). It was found that incubation of MNL with PMA resulted in a time- and concentration-dependent desensitization of isoproterenol-induced adenylate cyclase activity. However, the effect of PMA was not restricted to the beta-adrenergic receptor system, since basal adenylate cyclase activity and histamine-, prostaglandin E1-, 5'-guanylylimidodiphosphate (GppNHp)-, and NaF-stimulated values were also reduced. By contrast, no effect was found on the forskolin-induced adenylate cyclase activity. The inactive phorbol ester, 4 alpha-phorbol 12,13-didecanoate had no effect on adenylate cyclase at all, suggesting that the observed PMA effect was specifically mediated by activation of protein kinase C. The reduced beta-adrenergic response induced by PMA was not associated with a reduced beta-adrenergic receptor number, indicating uncoupling of this receptor from adenylate cyclase. Isoproterenol competition curves for 3H-dihydroalprenolol binding to membranes from untreated and PMA-treated cells demonstrated that the uncoupling was due to a reduced ability of the agonist to promote formation of the guanine nucleotide-sensitive high affinity state of the receptor. The results indicate that PMA may cause desensitization of catecholamine-responsive adenylate cyclase in MNL, and that the major locus of alteration is the guanine nucleotide regulatory protein.
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PMID:Phorbol 12-myristate 13-acetate induces beta-adrenergic receptor uncoupling and non-specific desensitization of adenylate cyclase in human mononuclear leukocytes. 302 44


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