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 present study was undertaken to determine how the responses to contractile agents are altered in aortas from rats with streptozotocin-induced diabetes and to explore the possible mechanisms of the altered responses in diabetes. Rats were given an intravenous injection of 45 mg/kg streptozotocin. Eight to 12 weeks after treatment, aortas were isolated and set up for measurement of isometric tension. Diabetic aortas exhibited significantly lesser contractions in response to high K+ than those from age-matched controls. Furthermore, the Ca2+ channel agonist Bay K 8644 was not able to consistently contract diabetic aortas even when they were partially depolarized by an elevation of the extracellular K+ concentration to 15 mM where the agonist produced concentration-dependent contractions in all control aortas. On the other hand, the contractile responses to norepinephrine, 5-hydroxytryptamine, endothelin-1 and U46619 were significantly enhanced in diabetic rat aortas. All of the enhanced responses of diabetic aortas were completely eliminated in the presence of the Ca2+ channel antagonist nifedipine. The contractile responses of aortas from both control and diabetic rats to these agonists were abolished or strongly inhibited by the protein kinase C inhibitor staurosporine, and no significant difference was found in the magnitude of the contractile responses of aortas between control and diabetic rats to the agonists in the presence of staurosporine. In diabetic aortas, the protein kinase C activators phorbol 12, 13-dibutyrate and 12-O-tetradecanoylphorbol 13-acetate elicited a delayed, sharply developing rise in tension following the initial, gradually developing contraction, while these agents produced only the initial, slowly developing contraction in control aortas. As a result, the contractions induced by phorbol esters were greater in diabetic aortas than in controls. The enhanced contractile responses of diabetic aortas to phorbol esters were not observed in Ca(2+)-free medium or in the presence of nifedipine. In Ca(2+)-free medium, the transient contraction induced by caffeine was significantly diminished in diabetic aortas, in contrast to the phasic contraction by norepinephrine which was similarly observed in control and diabetic aortas. These results indicate that the extracellular Ca(2+)-dependent contractions elicited by receptor activation are enhanced in aortas from diabetic rats, and this is presumably related to a greater influx of Ca2+ through transmembrane Ca2+ channels as a consequence of increased protein kinase C-activated processes. On the other hand, the contractions associated with depolarization-evoked activation of Ca2+ channels are diminished in diabetic aortas, possibly due to an alteration in activation of the channels by membrane depolarization, and Ca(2+)-induced Ca2+ release from intracellular stores appears to be impaired in diabetes.
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PMID:[Pharmacological studies on alterations in contractile reactivity in aortas isolated from experimental diabetic rats]. 946 17

Changes in contractile force were measured during isometric contraction of the bovine middle cerebral artery caused by stimulation of various receptors and by application of high K+, caffeine, and protein kinase C (PKC)-activators. The protein tyrosine kinase (PTK)-inhibitors, such as genistein and tyrphostin, were applied before testing the effect on the contractions or during the maximal plateau of the contraction. The contractions induced by serotonin, prostaglandin F2 alpha, endothelin-1, and thromboxane A2 were significantly and dose-dependently depressed by the PTK-inhibitors (IC50 2-15 microM). In contrast, contractions were significantly augmented by 1 microM pervanadate, an inhibitor of phosphoprotein tyrosine phosphatase. Lineweaver-Burk plotting of the dose-response curves with an increase in inhibitor concentration indicated that the receptor affinity for each agonist remained unchanged in spite of marked depression of the responses. Although the effect was not significant, contractions induced by both high K+ and caffeine were also depressed slightly by PTK-inhibitors in the same range of concentrations used for receptor-induced contractions. Contractions induced by PKC-activators, such as 1-oleoyl-2-acetyl-sn-glycerol and phorbol-12,13-diacetate, were significantly depressed by PTK-inhibitors at concentrations similar to those used for receptor-induced contractions. The results suggest that receptor stimulations which produce sequential activation of phospholipase C and PKC can activate PTK and trigger the so-called "PTK-cascade" causing a sustained or long-lasting contraction similar to the cerebral vasospasm observed clinically.
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PMID:Modulatory role of protein tyrosine kinase activation in the receptor-induced contractions of the bovine cerebral artery. 955 33

1. The role of protein kinase C (PKC) in mediating the action of kappa-receptor stimulation on intracellular Ca2+ and cyclic AMP production was determined by studying the effects of trans-(+/-)-3,4-dichloro-N-methyl-N-(2-[1-pyrrolidinyl] cyclohexyl) benzeneacetamide methanesulphonate (U50,488H), a selective kappa-receptor agonist, and phorbol 12-myristate 13-acetate (PMA), a PKC agonist, on the electrically-induced [Ca2+]i transient and forskolin-stimulated cyclic AMP accumulation in the presence and absence of a PKC antagonist, staurosporine or chelerythrine, in the single rat ventricular myocyte. 2. U50,488H at 2.5-40 microM decreased both the electrically-induced [Ca2+]i transient and forskolin-stimulated cyclic AMP accumulation dose-dependently, effects which PMA mimicked. The effects of the kappa-agonist, that were blocked by a selective kappa-antagonist, nor-binaltorphimine, were significantly antagonized by the PKC antagonists, staurosporine and/or chelerythrine. The results indicate that PKC mediates the actions of kappa-receptor stimulation. 3. To determine whether the action of PKC was at the sarcoplasmic reticulum (SR) or not, the [Ca2+]i transient induced by caffeine, that depletes the SR of Ca2+, was used as an indicator of Ca2+ content in the SR. The caffeine-induced [Ca2+]i transient was significantly reduced by U50,488H at 20 microM. This effect of U50,488H on caffeine-induced [Ca2+]i transient was significantly attenuated by 1 microM chelerythrine, indicating that the action of PKC involves mobilization of Ca2+ from the SR. When the increase in IP3 production in response to K-receptor stimulation with U50,488H in the ventricular myocyte was determined, the effect of U50,488H was the same in the presence and absence of staurosporine, suggesting that the effect of PKC activation subsequent to kappa-receptor stimulation does not involve IP3. The observations suggest that PKC may act directly at the SR. 4. In conclusion, the present study has provided evidence for the first time that PKC may be involved in the action of kappa-receptor stimulation on Ca2+ in the SR and cyclic AMP production, both of which play an essential role in Ca2+ homeostasis in the heart.
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PMID:Effects of kappa-opioid receptor stimulation in the heart and the involvement of protein kinase C. 964 87

The effects of four epicatechin derivatives, (-) epicatechin, (-) epicatechin gallate, (-) epigallocatechin and (-) epigallocatechin gallate, isolated from jasmine green tea, on the contractions were studied in mesenteric arteries isolated from male Sprague-Dawley rats. All four derivatives (30-500 microM) non-competitively reduced the contractile response to phenylephrine in a concentration-dependent manner with epigallocatechin gallate being the most potent. The relaxant effects of epicatechin derivatives were unaffected by the ATP-sensitive K+ channel blocker glibenclamide (3 microM) or the Ca2+-activated K+ channel blocker charybdotoxin (100 nM). Four epicatechin derivatives also reduced the sustained contractions induced by phenylephrine (1 microM) and endothelin I (5 nM) in normal Krebs solution, whilst they did not relax the phorbol 12-myristate 13-acetate (TPA, 2 microM)-contracted arteries in the absence of extracellular Ca2+. In arteries contracted with 60 mM K+, each of epicatechins caused a relaxation. However, epicatechin derivatives did not affect the transient contraction induced by 100 microM caffeine in Ca2+-free solution. The present results suggest that epicatechin derivatives from green tea leaves relaxed rat mesenteric arteries probably by inhibiting Ca2+ influx. The protein kinase C-dependent contractile pathway and intracellular Ca2+ release may not be involved.
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PMID:Vasorelaxant effects of purified green tea epicatechin derivatives in rat mesenteric artery. 969 36

Trifluoperazine (TFP), the antagonist of calmodulin (CaM), significantly stimulated the capacitation and acrosome reaction of guinea pig spermatozoa at the concentration of 10-100 mumol/L, independent of the external Ca2+. Forskolin, dbcAMP and caffeine evidently promoted the occurrence of acrosome reaction of spermatozoa at early capacitation stage (5 h) in nonsynchronous system but not in synchronous system. If the spermatozoa were capacitated for 15 h in synchronous system, the above three drugs significantly stimulated acrosome reaction in a Ca(2+)-independent manner. Protein kinase C activators, i.e. phorbol 12-myristate 13-acetate (PMA) and phorbol 12,13-dibutyrate (PDB) did not influence the occurrence of acrosome reaction of spermatozoa at early capacitation stage, but significantly increased the acrosome reaction rate in capacitated spermatozoa in a Ca(2+)-independent manner. In contrast, PKC inhibitor staurosporine significantly inhibited the occurrence of acrosome reaction.
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PMID:Signal transduction pathways in guinea pig sperm. 977 51

With the use of histone III-S as a protein kinase C (PKC) substrate, the activities of total and Ca2+-independent PKC in frog skeletal muscle were measured, and their difference is designated Ca2+-dependent PKC. In resting muscle, the total PKC was almost equally associated with the cytosol and membrane, and the ratio of membrane to cytosol PKC was about 1. However, the distribution of PKC was subtype dependent. About 60% of Ca2+-dependent PKC was located in the cytosol, whereas Ca2+-independent PKC was mainly associated with the membrane. High potassium exposure not only caused a significant translocation of Ca2+-dependent PKC from the cytosol to the membrane, but also changed the distribution of Ca2+-independent PKC, although to a lesser extent. However, in the preparations exposed to caffeine, the translocation of PKC occurred only in a Ca2+-dependent subtype. In addition, the biphasic change in membrane-associated PKC seen in high K+ exposed muscles was absent with caffeine treatment. The possible mechanisms of these differences are discussed.
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PMID:Effects of high potassium and caffeine exposure on activities of Ca2+-dependent and Ca2+-independent protein kinase C in frog skeletal muscle. 979 55

In an effort to further understand the processes underlying hypoxic pulmonary vasoconstriction, we examined the mechanism by which sodium hydrosulfite (Na2S2O4), a potent reducing agent and oxygen scavenger, induces smooth muscle contraction. In rat pulmonary arterial strips, sodium hydrosulfite (10 mM) induced contractions that were 65.9 +/- 12.8% of the response to 60 mM KCl (n = 9 segments). Contractions were not inhibited by nisoldipine (5 microM) or by repeated stimulation with caffeine (10 mM), carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone (10 microM), or cyclopiazonic acid (10 microM), all of which eliminated responses to contractile agonists. Maximum force generation after exposure to sodium hydrosulfite was 0.123 +/- 0.013 mN in the presence of 1.8 mM calcium and 0.127 +/- 0.015 mN in the absence of calcium. Sodium hydrosulfite contractions in pulmonary arterial segments were not due to the generation of H2O2 and occurred in the presence of chelerythrine (10 microM), which blocked phorbol ester contractions, and solution hyperoxygenation. Similar contractile responses were obtained in rat aortic and tracheal smooth muscles. Finally, contractions occurred in the complete absence of an increase in myosin light chain phosphorylation. Therefore sodium hydrosulfite-induced smooth muscle contraction is not specific to pulmonary arterial smooth muscle, is independent of calcium and myosin light chain phosphorylation, and is not mediated by either hypoxia or protein kinase C.
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PMID:Sodium hydrosulfite contractions of smooth muscle are calcium and myosin phosphorylation independent. 981 16

The intracellular Ca2+ stores and the mechanisms of Ca2+ entry produced by norepinephrine (NE) were investigated in small mesenteric resistance arteries of the rat. In Ca2+-free medium, NE (10 microM) elicited a transient increase in both intracellular free Ca2+ concentration ([Ca2+]i) and tension that were both drastically reduced by caffeine and only partially reduced by the two sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) blockers thapsigargin and cyclopiazonic acid, despite the presence of SERCA2a and SERCA2b isoforms in the medial smooth muscle layer of the artery. After depletion of intracellular Ca2+ stores with 10 microM NE, addition of exogenous CaCl2 (2.5 mM) produced large and sustained increases in both [Ca2+]i and contraction of the arteries provided that the agonist was continuously present. In these conditions, the responses to CaCl2 were inhibited by the voltage-dependent Ca2+ entry blocker nitrendipine (1 microM), the putative inhibitor of receptor-operated Ca2+ entry SKF-96365 (30 microM), and NiCl2 (1 mM). The inhibition produced by SKF-96365 and NiCl2 was greater than that of nitrendipine. Also, the responses to CaCl2 were greatly reduced or abolished in the presence of the Na+/Ca2+ exchanger inhibitors 1,3-dimethyl-2-thiourea, 3',4'-dichlorobenzamil, MgCl2, and amiloride or after omission of NaCl in the medium. Also, protein kinase C inhibitors, calphostin C and staurosporine, and tyrosine kinase inhibitors, genistein and tyrphostin 23, both reduced the responses to CaCl2. The inhibitory effect of protein kinase C inhibitor and tyrosine kinase were additive. These results suggest that NE releases Ca2+ from intracellular stores that are caffeine sensitive and partially sensitive to SERCA inhibitors. They indicate that in addition to Ca2+ influx via nitrendipine-sensitive and SKF-96365-sensitive channels, Na+/Ca2+ exchanger participates in the CaCl2-induced contraction produced in NE-exposed vessels. The pathway leading to Ca2+ entry probably involves tyrosine kinase and protein kinase C. All the above mechanisms require ongoing receptor stimulation.
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PMID:Mechanism of Ca2+ release and entry during contraction elicited by norepinephrine in rat resistance arteries. 988 44

A high-speed imaging technique was used to investigate the effects of inhibitors and activators of protein kinase C (PKC) on the [Ca2+]i transients and contraction of fura-2 loaded rat ventricular cardiac myocytes. The amplitude of the [Ca2+]i transient was reduced following treatment with 100 nM phorbol 12,13-dibutyrate (PDBu), whereas the PKC inhibitors staurosporine (0.5 microM) and calphostin C (10 microM) increased [Ca2+]i transient amplitude, elevated basal [Ca2+]i and slowed the decay of the [Ca2+]i transient. These changes were paralleled by similar alterations in the rate and extent of cell shortening. The activity of nitrendipine-sensitive Ca2+ channels was monitored indirectly as the rate of Mn2+ quench of cytosolic fura-2 in electrically-paced cells. PDBu reduced Mn2+ influx by six-fold, whereas staurosporine and calphostin C increased the influx rate by eight-fold and seven-fold over basal quench, respectively. The caffeine releasable Ca2+ pool was reduced in the presence of PDBu and increased transiently in presence of staurosporine. The effects of PKC activation and inhibition on sarcoplasmic reticulum Ca2+ content may be secondary to alterations of sarcolemmal Ca2+ influx. However, the PKC inhibitors also decreased the rate of sarcoplasmic reticulum Ca2+ uptake in permeabilized myocytes, suggesting that a direct effect of PKC on the sarcoplasmic reticulum may contribute to the prolongation of the [Ca2+]i transient under these conditions. The present work demonstrates that basal PKC activity has a potent depressant effect, mediated primarily through inhibition of sarcolemmal Ca2+ influx, which may play a key role in setting the basal tone of cardiac muscle.
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PMID:Tonic regulation of excitation-contraction coupling by basal protein kinase C activity in isolated cardiac myocytes. 999 May 31

An unusual inward current which is slowly elicited in the Xenopus oocyte membrane during sustained depolarization is reportedly carried by Na+. It is thought that Na+ selective channels are in some way induced to become voltage-sensitive by the depolarization. Earlier studies report that the induction process involves a phospholipase C and a protein kinase C as well as calcium ions. The present work investigated the origins of this calcium in the oocyte. We show that injection of the powerful Ca2+ chelator (BAPTA) in the oocyte, before induction of the Na+ channels, prevented the appearance of the Na+ current, confirming an important role for [Ca2+]i. However, in oocytes perfused with Ca2+ -free medium, induction of the channels could still be obtained, indicating that induction did not depend upon the entry of external Ca2+. Downmodulation of Ca2+ release from inositol 1,4,5-trisphosphate (InsP3)-sensitive stores with caffeine and with a low molecular weight heparin resulted in decreased or no Na+ currents. The results are discussed in terms of the contributions from other endogenous calcium-dependent conductances which can influence the Na+ current amplitudes and time courses. The results presented support the idea that intracellular Ca2+ increase principally due to Ca2+ released from InsP3-sensitive stores is needed by the enzyme systems to produce the depolarization-induced activation of the Na+ conductance in the Xenopus oocyte.
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PMID:Induction of Na+ channel voltage sensitivity in Xenopus oocytes depends on Ca2+ mobilization. 1004 90


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