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)

Changes in the activity of the brush-border Na-H antiporter are accompanied by parallel changes in the activity of the Na-HCO3 cotransporter. Adenosine 3',5'-cyclic monophosphate (cAMP) and calmodulin inhibit the Na-H antiporter, whereas protein kinase C (PKC) stimulates it. We hypothesized that cAMP, calmodulin, and PKC should have similar effects on the Na-HCO3 cotransporter activity. Phosphorylated renal basolateral membranes were treated with either cAMP, calmodulin, or phorbol ester. cAMP, 1 microM, inhibited HCO3-dependent 22Na uptake without affecting 22Na uptake in presence of gluconate, suggesting that cAMP inhibits Na-HCO3 cotransporter activity without altering diffusive 22Na uptake. The effect of cAMP to inhibit the Na-HCO3 cotransporter could also be elicited by the catalytic subunit of cAMP, and this inhibitory effect was prevented by the protein kinase A (PKA) inhibitor. Calmodulin (1 microM), in presence of Ca, also inhibited HCO3-dependent 22Na uptake in presence of HCO3, whereas 22Na uptake in the presence of gluconate was unchanged. The inhibitory effect of calmodulin on HCO3-dependent 22Na uptake was prevented by N-(4-aminobutyl)-5-chloro-2-naphthalene sulfonamide (W-13), an inhibitor of calmodulin. Phorbol 12-myristate 13-acetate and PKC stimulated Na-HCO3 cotransporter activity, whereas the inactive analogue, 4 alpha-phorbol, failed to elicit such a stimulation. Basolateral membranes displayed cAMP-dependent and Ca-dependent protein kinase activities. Thus PKA and Ca-dependent protein kinases regulate the activity of the Na-HCO3 cotransporter and suggest that hormones that act through these systems modulate the activity of the Na-HCO3 cotransporter.
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PMID:Regulation of the renal Na-HCO3 cotransporter by cAMP and Ca-dependent protein kinases. 131 5

We examined the effects of mammalian lignans, enterolactone, prestegane B and 2,3-dibenzylbutane-1,4-diol (DBB) on superoxide production and luminol-dependent chemiluminescence (LCL) response in human polymorphonuclear leucocytes (PMNs). The three lignans had no direct effect on the responses of human PMNs. DBB and prestegane B enhanced the superoxide production and LCL response induced by formylmethionyl-leucyl-phenylalanine (fMLP), but enterolactone inhibited fMLP-induced effects. The effects of DBB were stronger than those of prestegane B and the effects of DBB were inhibited by bromophenacyl bromide, mepacrine, N-(6-aminophenyl)-5-chloro-1-naphthalene, sulphonamide and trifluoroperazine, but not by gossypol, nordihydroguaretic acid, indomethacin, staurosporine, 1-(5-isoquinolinesulphonyl)-2-methylpiperazine dihydrochloride or (R,S)-2-methoxy-3-(octadecyl-carbamoyloxy)-propyl-2-(2-thiazoli o)-ethylphosphate. These results suggest that DBB primes the responses of human PMNs, and the priming effect is caused by the activation of phospholipase A2--and Ca(2+)-calmodulin-pathways, but not by the activation of lipoxygenase, cyclo-oxygenase and protein kinase C or by the release of platelet activating factor.
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PMID:Effect of mammalian lignans on fMLP-induced oxidative bursts in human polymorphonuclear leucocytes. 136 May 14

The present studies examined effects of ATP depletion and calmodulin antagonism on stimulation of Na(+)-H+ exchange by cytosolic acidification in renal epithelial cells (LLC-PK1). ATP depletion significantly inhibited both amiloride-sensitive 22Na+ uptake (P less than 0.001; n = 12) and Na(+)-dependent intracellular pH (pHi) recovery in 2',7'-bis (carboxyethyl)-5(6)-carboxyfluorescein acetoxymethylester (BCECF/AM)-loaded cells. Calmodulin antagonists, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) and calmidazolium, both caused a concentration-dependent inhibition of Na(+)-H+ exchange activity. The W-7-induced inhibition of Na(+)-H+ exchange occurred in cells incubated for 24 h with phorbol 12-myristate 13-acetate, indicating that the effect of W-7 was not mediated by protein kinase C inhibition. Both W-7 and ATP depletion shifted the pHi dependence of the antiporter, and ATP depletion also reduced the maximal activity. In LLC-PK1/CL4 cells grown on permeable filters, W-7 inhibited the cytosolic acidification-stimulated basolateral exchanger by 54 +/- 5% (P less than 0.005; n = 7) and, in contrast, stimulated the apical exchanger by 28 +/- 13% (P less than 0.05; n = 6). ATP depletion significantly inhibited apical Na(+)-H+ exchange. These results suggest that an ATP-Ca(2+)-calmodulin-dependent process is involved in regulation of Na(+)-H+ exchange in LLC-PK1 cells. A Ca(2+)-calmodulin-dependent process activated the amiloride-sensitive basolateral Na(+)-H+ exchanger and inhibited the amiloride-resistant apical antiporter. Phosphorylation of these two Na(+)-H+ exchangers or regulatory proteins by a Ca(2+)-calmodulin-dependent protein kinase may mediate this differential regulation.
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PMID:Regulation of Na(+)-H+ exchange by ATP depletion and calmodulin antagonism in renal epithelial cells. 165 80

The design and synthesis of a series of novel inhibitors of protein kinase C (PKC) is described. These 2,3-bisarylmaleimides were derived from the structural lead provided by the indolocarbazoles, staurosporine and K252a. Optimum activity required the imide NH, both carbonyl groups, and the olefinic bond of the maleimide ring. 2,3-Bisindolylmaleimides were the most active, and the potency of these was improved by a chloro substituent at the 5-position of one indole ring (compound 28, IC50 0.11 microM). In a series of (phenylindolyl)maleimides, nitro compound 74 was most active (IC50 0.67 microM). Naphthalene 19 and benzothiophene 21 showed greater than 100-fold selectivity for inhibition of PKC over the closely related cAMP-dependent protein kinase (PKA).
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PMID:Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. 173 26

The effect of azelastine, an orally effective antiasthmatic antiallergic drug on the generation of oxygen-derived free radicals in phagocytes was investigated using different chemiluminescence-assays. The chemiluminescence (CL) of both human polymorphonuclear granulocytes (PMNL) and guinea-pig alveolar macrophages (AM) was induced either by phorbol myristate acetate (PMA) or zymosan and amplified either by lucigenin or DMNH (7-dimethylamino-naphthalene-1,2-dicarbonic-acidhydrazide). The inhibitory effect of azelastine was dependent on the inducer employed and the condition and type of cells used. Azelastine reduced PMA-induced CL concentration-dependently in both PMNL (IC30 = 3.9 microM) and AM (IC30 = 9.8 microM). In AM zymosan-induced CL was inhibited 21.7% by 10 microM azelastine, whereas in PMNL it remained unchanged up to 10 microM azelastine. Azelastine has a significantly stronger inhibitory effect (IC30 = 4.2 microM) on oxygen free radical generation in AM primed by fetal calf serum than in unprimed AM. Based on present results it is likely that azelastine inhibits oxygen-derived free radical generation by interaction with protein kinase C.
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PMID:Inhibition of chemiluminescence in granulocytes and alveolar macrophages by azelastine. 208 39

PMA causes rapid down-modulation of CD4 molecules on murine immature thymocytes, human PBL, and CD4-positive human tumor cell lines, but not on murine peripheral lymphocytes. The mechanisms of phorbol ester-induced down modulation of CD4 molecules, however, have not been elucidated. To determine how PMA down-modulates CD4 expression by T lymphocytes, we studied the ability of inhibitors of protein kinase C, calmodulin, actin, and tubulin to block PMA-induced modulation of CD4 in several murine and human cell types. We also tested the ability of intracellular and extracellular calcium chelators to block CD4 internalization. There was marked variability in the degree of PMA-induced down-modulation of CD4 among various cell types. The effects of PMA on CD4 expression were greater for murine thymocytes, for human PBL, and for the human lymphoblastic leukemia cell line, MOLT-3, than for any of the other cell types studied. The protein kinase C inhibitor, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine, blocked phosphorylation but not internalization of CD4 molecules induced by PMA. Therefore, phosphorylation of CD4 molecules by protein kinase C is not required for the internalization of the molecules. Internalization was blocked by both inhibitors of calmodulin, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide, and trifluoperazine. PMA-induced internalization of CD4 was blocked by Quin-2 AM, which chelates intracellular calcium. EGTA, which chelates extracellular calcium, did not block internalization. Inhibitors of actin or tubulin did not block internalization. These results suggest that PMA-induced modulation of CD4 can occur in the absence of phosphorylation of the CD4 molecules and is calmodulin and intracellular calcium dependent.
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PMID:Phorbol myristate acetate-induced down-modulation of CD4 is dependent on calmodulin and intracellular calcium. 210 10

The mechanisms by which phospholipase C from Clostridium perfringens stimulates release of arachidonic acid (AA) in cultured intestinal epithelial cells (INT-407) were investigated. INT-407 cells were first allowed to incorporate 14C-labeled AA into their phospholipids; the labeled cells were then exposed to phospholipase C, and the release of free 14C-AA was determined. Phospholipase C caused a rapid (3 min) intracellular rise of free 14C-AA, followed by a considerable, dose- and time-dependent release of 14C-AA into the extracellular medium. For comparison, the calcium ionophore A23187 also caused a rapid mobilization of free 14C-AA, but a much lower extracellular 14C-AA release than phospholipase C during longer (1 h) incubation. The 14C-AA release was accompanied by a degradation of 14C-myo-inositol-labeled phosphatidylinositols and was reduced by the protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H-7). Both phospholipase C- and A23187-stimulated 14C-AA release was associated with degradation of phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol and was reduced by nordihydroguaiaretic acid and 4-bromophenacyl bromide, two known phospholipase A2 inhibitors. In addition, the 14C-AA release was reduced by the calmodulin inhibitors trifluoperazine, compound 48/80, and N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7). These findings indicate that phospholipase C from C. perfringens stimulates phospholipase A2-mediated AA release from human intestinal epithelial cells and suggest that this stimulation is brought about via processes involving phosphatidylinositol breakdown and activation of calmodulin and protein kinase C. It is possible that this phospholipase C-evoked AA release may contribute to the mucosal pathologic condition in diseases with altered intestinal microbial flora.
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PMID:Phospholipase C from Clostridium perfringens stimulates phospholipase A2-mediated arachidonic acid release in cultured intestinal epithelial cells (INT 407). 211 Jun 84

Induction of interferon-beta (IFN-beta) in human (BG-9), simian (CV-1) and mouse (L-929) cell lines by Sendai virus and by poly(rI). poly(rC) has been studied for its possible dependence on protein kinase C (PKC) through the use of pharmacological inhibitors (K252a and H-7) of PKC. Exposure of BG-9, CV-1 or L-929 cells to K252a (greater than or equal to 0.025 microM), a staurosporine derivative, 24 h before or after induction of IFN with poly(rI).poly(rC), inhibited by greater than 95% the production of IFN-beta. In contrast, virus-induced IFN production was enhanced threefold or more by K252a in BG-9 and L-929 but not in CV-1 cells. A naphthalene sulphonamide inhibitor of PKC, H-7, at greater than or equal to 5 microM, decreased poly(rI).poly(rC)-induced IFN production in BG-9 and CV-1 cells by 75 to 94%, but had no effect on IFN production in L-929 cells. Viral induction of IFN was not affected significantly by H-7 in BG-9, CV-1 and L-929 cells. In contrast to these results, the calmodulin inhibitor, trifluoperazine (5 to 15 microM) did not affect IFN-beta production by poly(rI).poly(rC) but significantly enhanced IFN production by Sendai virus in both human and murine cell lines. Thus, in human and simian fibroblasts the induction of IFN-beta by poly(rI).poly(rC) appears to be PKC-dependent, whereas viral induction of IFN-beta is not. Results with K252a implicate PKC in non-viral induction of IFN in mouse fibroblasts, as well. Direct measurements of PKC activity in BG-9 cells exposed to several concentrations of K252a showed that the membrane PKC activity is significantly more sensitive to inhibition by K252a than is cytosolic PKC activity. In L-929 cells, K252a inhibited membrane PKC activity similarly, but was less effective as an inhibitor of cytosolic enzyme activity than in BG-9. These studies support an integral role for PKC activity, particularly membrane-associated activity, in non-viral [poly(rI).poly(rC)] induction of IFN-beta in human, simian and mouse fibroblasts.
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PMID:Effect of protein kinase C inhibitors on interferon-beta production by viral and non-viral inducers. 217 82

Parietal cells are a major source of gastric mucosal prostaglandins in various species. We examined cholinergic stimulation of prostaglandin E2 (PGE2) release from human parietal cells; using activators of the protein kinase C we attempted to get an indirect insight into cellular mechanisms which control PGE2 release. Gastric mucosal specimens were obtained at surgery and the cells were dispersed by collagenase and pronase E. Parietal cells were enriched to 65-80% by a Percoll gradient, and were incubated for 30 min. PGE2 release into the medium (radioimmunoassay) was 74-126 pg/10(6) cells/30 min under basal conditions and was 2.6-fold increased by carbachol (10(-5) and 10(-4) M). Similarly, PGE2 release was stimulated by phospholipase C (20-200 mU/ml, 364% above basal), 1-oleoyl-2-acetyl-sn-glycerol (10(-9)-10(-5) M, 229%), 12-O-tetradecanoylphorbol-13-acetate (TPA; 10(-9)-10(-5) M, 283%) and calcium ionophore A23187 (10(-7)-10(-5) M, 219%). Simultaneous presence of A23187 and TPA synergistically induced stimulation which was slightly higher than the sum of the individual responses. N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide W-7, a putative calmodulin antagonist, inhibited TPA-induced PGE2 release at concentrations regarded specific for blocking calmodulin (IC50 = 1.5 X 0(-6) M). We conclude that in human parietal cells PGE2 is released upon cholinergic stimulation and that phospholipase C and protein kinase C are involved in the control of PGE2 release. We speculate that calmodulin might interact with a protein phosphorylated by protein kinase C to cause PGE2 release.
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PMID:Potential mediation of prostaglandin E2 release from isolated human parietal cells by protein kinase C. 222 20

We studied the cholinergic stimulation of isolated and enriched rat parietal cells. H+ production was indirectly measured by the uptake of 14C-aminopyrine into the parietal cells. Stimulation by carbachol required the presence of extracellular Ca2+ not only in the initial phase but also during the sustained phase of a 100-min incubation period. The response to carbachol was prevented by the Ca2+ entry blocker lanthanum IC50: 1.5 X 10(-7) mol/l). Furthermore, the dependence on Ca2+ influx of cholinergic stimulation was demonstrated by a 269% increase in total intracellular Ca2+ in response to carbachol, as determined by optical emission spectrometry. The naphthalene sulfonamides W7 and W5 which bind calmodulin and thus block the intracellular transduction of Ca2+ effects also inhibited a carbachol-induced H+ production. In the following experiments we studied the effect of agents which activate the protein kinase C, an enzyme which is supposed to play a key role in intracellular signal transduction of Ca2+-dependent effects. Phospholipase C is supposed to activate protein kinase C via induction of the phosphoinositol breakdown. In our preparation of isolated rat parietal cells, phospholipase C (4-100 mU/ml) exerted inhibition instead of amplification of the response to 10(-4) mol/l carbachol. Similarly, the direct activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate or by 1-oleoyl-2-acetyl-sn-glycerol (both tested at 10(-7) to 10(-5) mol/l) reduced the submaximal and maximal response to 10(-5) or 10(-4) mol/l carbachol. We conclude that the cholinergic stimulation of rat parietal cells is dependent on the influx of extracellular Ca2+. Calmodulin seems to mediate intracellular Ca2+ effects during cholinergic stimulation. The activation of protein kinase C impairs carbachol-induced H+ production instead of augmenting the response. This might be due to an already maximal activation of protein kinase C by carbachol alone or to autoregulatory down-regulation by the protein kinase C of muscarinic parietal-cell receptors.
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PMID:Cholinergic stimulation of isolated rat parietal cells: role of calcium, calmodulin and protein kinase C. 280 65


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