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 objective of this study was to determine whether adenosine A1 or A2 receptor was responsible for the regulation of protein kinase C (PKC) in porcine coronary artery and its coupling to G-protein. Endothelium denuded arterial rings were incubated with PDBu (200 nM) in the presence or absence of adenosine receptor agonists and antagonists for 1 day. Following incubation, the arterial rings were contracted with increasing concentrations of endothelin-1 (ET-1) (10(-10)-10(-7) M). Arteries incubated with PDBu alone failed to produce contraction in response to ET-1. On the contrary, inclusion of A1 receptor agonist ENBA at 10(-9) M in the incubation media with PDBu protected against the PDBu induced blunting of the ET-1 contractions by 50%. Incubation with ENBA alone increased ET-1 dependent contractions by about 2 fold. Inclusion of A1 receptor antagonist, N0861 at 10(-6) M along with PDBu and ENBA, completely blocked the protective effect of ENBA against the PDBu induced attenuation of ET-1 contractions. N0861 also completely blocked the increase in ET-1 contractions in the arterial rings incubated with ENBA alone. Another A1 receptor antagonist DPCPX also produced similar results as N0861. On the contrary, arterial rings incubated with relatively specific A2 receptor agonist CGS 21680 at 10(-4) M did not produce any protection against PDBu induced blunting of the ET-1 contractions. Incubation with CGS 21680 alone also did not significantly alter the ET-1 contractions. Interestingly, inclusion of A2 receptor antagonist DMPX at 10(-4) M in the incubation media along with CGS 21680 mimicked the effects of ENBA alone i.e. produced protection against PDBu and enhanced ET-1 contractions. Incubation of the arteries with ENBA alone caused an accumulation of PKC levels, whereas, incubation with CGS 21680 had no significant effect on PKC levels. To study the coupling of adenosine receptor with G-protein, the tissue was incubated for one day with cholera (CT) or pertussis toxin (PT) in the presence or absence or ENBA and PDBu as described above. Incubation with PT blocked the protective effect of ENBA against PDBu as well as the elevation of ET-1 response when incubated with ENBA alone. On the contrary, incubation with CT did not produce any significant effect on ENBA responses. These results indicate that PKC is modulated by adenosine via A1 adenosine receptors and through a PT sensitive G-protein.
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PMID:Modulation of protein kinase C by adenosine: involvement of adenosine A1 receptor-pertussis toxin sensitive nucleotide binding protein system. 856 49

Ischemic preconditioning has been shown to involve the activation of adenosine receptors, protein kinase C (PKC), and ATP-sensitive K+ (K ATP) channels. We investigated the effects of PKC activation and adenosine on K(ATP) current (I KATP) and action potentials in isolated rabbit ventricular myocytes. Responses to pinacidil (100 to 400 micromol/L), an opener of K(ATP) channels, were markedly increased by preexposure to the PKC activator phorbol 12-myristate 13-acetate (PMA, 100 nmol/L). I(KATP) measured at 0 mV was increased by PMA pretreatment from 0.55 +/- 0.32 to 3.25 +/- 0.47 nA (n=6, P < .01). We next determined whether PKC activation abbreviates the time required to turn on I(KATP) developed after an average of 15.1 +/- 2.4 minutes (n=8). Ten-minute pretreatment with PMA alone (PMA+MI) did not significantly alter this latency (11.9 +/- 2.0 minutes, n=8). Since adenosine receptor activation has been shown to play an important role in the preconditioning response, two groups of myocytes were studied with adenosine (10 micromol/L) included during MI. Without PMA, adenosine alone (MI+Ado) did not affect the latency to develop I(KATP) (12.3 +/- 1.5 minutes, n=8). However, if cells were pretreated with PMA and then subjected to MI in the presence of adenosine (PMA+MI+Ado), the latency was greatly shortened to 5.5 +/- 1.6 minutes (n=8;P < .02 versus MI, PMA+MI, and MI+Ado groups). This effect could not be reproduced by an inactive phorbol but was completely abolished by the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline. The opening of K(ATP) channels may be cardioprotective because of the abbreviation of action potential duration (APD) during ischemia. Therefore, we tested whether PKC activation could modify the time course of APD shortening during MI. Consistent with the ionic current measurements, PMA pretreatment significantly accelerated APD shortening, but only when adenosine (10 micromol/L) was included during MI. The effects were not attributable to accelerated ATP consumption: PMA pretreatment did not alter the time required to induce rigor during MI, whether or not adenosine was included. Our results indicate that PKC activation increases the I(KATP) Induced by pinacidil or by MI. The latter effect requires concomitant adenosine receptor activation. The synergistic modulation of I(KATP) by PKC and adenosine provides an explicit basis for current paradigms of ischemic preconditioning.
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PMID:Synergistic modulation of ATP-sensitive K+ currents by protein kinase C and adenosine. Implications for ischemic preconditioning. 859 3

We tested the hypothesis that anoxic preconditioning could protect coronary endothelial cells against anoxic and reoxygenation injury and that this preconditioning effect could be mediated by an adenosine A2 receptor via the protein kinase C (PKC) pathway. Cells were preconditioned with 10-minute anoxia and 10-minute reoxygenation and were then subjected to anoxia for 60 minutes, followed by 120 minutes of reoxygenation. In some groups, the preconditioning effect was prevented by 8-sulfophenyltheophylline (SPT [50 mumol/L], a nonselective adenosine receptor antagonist), or calphostin C (100 nmol/L, a PKC inhibitor). In other groups, 2-p-(2-carboxyethyl)phenethylamino-5'N-ethylcarboxyamido- adenosine (CGS-21680 [20 nmol/L], an adenosine A2 receptor agonist, R-(--)-N6-(2-phenylisopropyl)-adenosine (R-PIA [50 nmol/L], an adenosine A1 receptor agonist), or 4 beta-phorbol 12-myristate 13-acetate (PMA [100 nmol/L], a PKC activator) was given as a pretreatment to mimic the preconditioning effect. Endothelial cells were also pretreated with 100 nmol/L calphostin C to confirm whether inhibition of PKC can block the effects of adenosine A2 receptor activation by CGS-21680 on anoxia and reoxygenation injury. Preconditioning reduced LDH release, increased adenosine release, promoted translocation of PKC from cytosol to membrane, increased cell viability, and preserved ATP content and cell morphology. Pretreatment with either CGS-21680 or PMA resulted in protection similar to that seen with anoxic preconditioning. The protection was totally abolished by SPT or calphostin C. The results suggest that (1) preconditioning protects coronary endothelial cells against anoxia and reoxygenation injury, (2) the protection is probably mediated by activation of adenosine A2 receptors through the PKC pathway, and (3) the preservation of endothelial cells may be one of the mechanisms of myocardial preconditioning.
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PMID:Preconditioning of bovine endothelial cells. The protective effect is mediated by an adenosine A2 receptor through a protein kinase C signaling pathway. 860 8

Adenosine A1 receptor densities were increased in cultured LLC-PK1 and OK cells by chronic treatment with the adenosine receptor antagonists 1,3,7-trimethylxanthine (caffeine, 1 mM) and 1,3-dimethyl-8-cyclopentylxanthine [cyclopentyltheophylline (CPT), < or = 0.4 mM], respectively. The A1 receptor number per cell was increased twofold by 10-day treatments with 1 mM caffeine or 0.1 mM CPT, and the sodium-coupled glucose uptake was augmented twofold by 1 mM caffeine and sevenfold by 0.1 microM CPT (higher doses of CPT were progressively less stimulatory). Glucose uptake was blocked by acute (2-h) treatment with CPT, adenosine deaminase, or calphostin C. Caffeine (1 mM) or CPT (> or = 0.1 mM) inhibited cell proliferation for the first 10 days, then cell growth assumed a normal proliferative rate despite continued presence of antagonist. Cytosolic protein kinase C (PKC) beta-isoform immunoactivity and PKC-beta II mRNA were elevated at least twofold during 10 days of 0.1 mM CPT or 1 mM caffeine treatment. The sustained elevation in sodium-glucose symport and PKC activity observed with adenosine receptor antagonists was similar to acute (2-h) effects of the adenosine A1 agonist R(-)-N6-phenylisopropyladenosine (R-PIA, 0.1-1 microM). Moreover, cell proliferation was increased by adenosine (0.1 microM R-PIA), whereas Na-K-adenosinetriphosphatase activity was unaltered with chronic antagonist or acute adenosine treatments. Caffeine treatment may have some non-adenosine A1 receptor-mediated actions, because it slightly (30%) augmented protein kinase A activity. It is concluded that chronic exposure of proximal tubule cells to caffeine or CPT augments PKC and sodium-glucose transport but retards cell proliferation mainly via adenosine A1 receptor-mediated mechanisms.
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PMID:Upregulated renal adenosine A1 receptors augment PKC and glucose transport but inhibit proliferation. 877 86

Formycin A augments insulin release evoked by glucose (5.6 mm or more), this effect not being rapidly reversible. The mechanism responsible for the insulinotropic action of formycin A was investigated in isolated pancreatic islets. It could not be ascribed to facilitation of glucose metabolism. On the contrary, formycin A inhibited glucose oxidation, lowered ATP content, and impaired glucose-stimulated protein biosynthesis. The insulinotropic action of formycin A was apparently attributable to its conversion to formycin A 5'-triphosphate, both this process and the secretory response to formycin A being abolished by the inhibitor of adenosine kinase 5-iodotubercidin. In agreement with the latter view, adenosine receptor antagonists such as 8-cyclopentyl-1, 3-dipropylxanthine and 3,7-dimethyl-1-propargylxanthine failed to suppress and, instead, augmented the insulinotropic action of formycin A. Unexpectedly, however, formycin A failed to decrease 86Rb efflux, this coinciding with a low efficiency of formycin A 5'-triphosphate to inhibit KATP-channel activity in excised membranes and with the fact that formycin A increased gliben-clamide-stimulated insulin release. The secretory response to formycin A represented a Ca2+-dependent process suppressed in the absence of extracellular Ca2+ or presence of verapamil and associated with an increased net uptake of 45Ca. Nevertheless, the view that formycin A exerts any major effect upon intracellular Ca2+ redistribution, protein kinase C activity, or cyclic AMP net production also met with objections such as the minor secretory effect of formycin A in islets exposed to a high concentration of K+ in the presence of a diazoxide analog, the resistance of formycin A insulinotropic action to bisindolylmaleimide, the poor increase of cyclic AMP content in formycin A-stimulated islets, and the pronounced enhancement by forskolin or theophylline of insulin release from islets exposed to formycin A. It is concluded, therefore, that the mechanism of action of formycin A in the pancreatic beta-cell remains to be elucidated.
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PMID:The riddle of formycin A insulinotropic action. 881 26

Adenosine, synthesized by ecto-5'-nucleotidase, is cardioprotective against ischemia and reperfusion injury. We have previously reported that activation of protein kinase C increases ecto-5'-nucleotidase activity of the rat cardiomyocytes, raising the possibility that activation of protein kinase C protects cardiomyocytes from the irreversible cellular injury via activation of ecto-5'-nucleotidase. To test this hypothesis, cardiomyocytes were isolated from adult male Wistar rats and suspended in modified HEPES-Tyrode buffer solution. The cardiomyocytes were incubated with and without exposure to methoxamine (1 x 10(-6) mol/l) or phorbol 12-myristate 13-acetate (PMA. 1 x 10(-8) mol/l). Ecto-5'-nucleotidase activity increased 15 min after the onset of an exposure to either methoxamine or PMA. Adenosine release during hypoxia and reperfusion was augmented in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated cardiomyocytes, which was inhibited by alpha, beta-methyleneadenosine 5'-diphosphate (AOPCP), an inhibitor of ecto-5'-nucleotidase. Irreversible cellular injury assessed by the extent of release of lactate dehydrogenase and the trypan blue exclusion test following 60 min of hypoxia and 60 min of reoxygenation was attenuated in the methoxamine- and PMA-pretreated cardiomyocytes compared with the untreated group, which was also blunted by AOPCP and 8-sulfophenyltheophylline, an adenosine receptor antagonist. An adenosine A1 receptor agonist, N6-cyclohexyladenosine, restored the cardioprotection under the treatment with PMA and AOPCP. We conclude that activation of ecto-5'-nucleotidase via protein kinase C contributes to the attenuation of the irreversible injury of the rat cardiomyocytes due to hypoxia and reoxygenation.
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PMID:Activation of ecto-5'-nucleotidase by protein kinase C attenuates irreversible cellular injury due to hypoxia and reoxygenation in rat cardiomyocytes. 889 53

The induction of programmed cell death by adenosine was investigated in cultured rat microglial cells using the enzyme-linked immunosorbent assay (ELISA) for determining DNA fragmentation. Twelve hours exposure to micromolar levels of the unselective adenosine receptor agonist 2-chloro-adenosine led to the appearance of DNA fragments in the cytosolic fraction preceding damage of the plasma membrane. This effect was still seen in the presence of an adenosine uptake blocker. Conventional A1, A2 or A3 agonists and antagonists were rather ineffective, suggesting mediation via an atypical adenosine receptor subtype. Microglial DNA fragmentation was inhibited by H-7 and staurosporine but not by dibutyryl-cyclic AMP, pointing to a protein kinase C linked mechanism. Such an induction of programmed cell death by an elevation of the extracellular adenosine concentration may provide an endogenous control mechanism to limit the function of activated microglial cells.
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PMID:Programmed cell death in rat microglia is controlled by extracellular adenosine. 894 35

Exposure of the heart to adenosine decreases heart rate and left ventricular developed pressure. However, little is known regarding the influence of adenosine on mechanical properties of isolated ventricular myocytes and the intracellular mechanism(s) by which adenosine acts. Therefore, in the present study we compared the effects of the adenosine receptor agonist R-phenylisopropyladenosine (R-PIA) and protein kinase C (PKC) activator dioctanoylglycerol (DOG) on Ca2+ sensitivity of tension, maximum isometric tension, and velocity of unloaded shortening (Vmax) in enzymatically isolated, drug-treated, and subsequently skinned ventricular myocytes. Neither R-PIA (100 microM) nor DOG (50 microM) affected Ca2+ sensitivity of tension or maximum isometric tension compared with controls. However, both R-PIA and DOG treatment caused approximately 25% decrease in Vmax during maximum activation compared with controls. This suggests adenosine and PKC decrease actin-myosin interaction through an alteration of myofilament proteins. The observed similarity of response after R-PIA and DOG treatment is consistent with the hypothesis that effects of adenosine are mediated by activation of the PKC pathway in isolated ventricular myocytes.
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PMID:Effects of adenosine and protein kinase C stimulation on mechanical properties of rat cardiac myocytes. 894 91

We have proposed that ischemic preconditioning in rabbit hearts is initiated by adenosine receptor stimulation resulting in activation of protein kinase C. If this theory is correct then any agonist which can activate PKC should also put the heart into a preconditioned state. This study sought to determine whether endothelin-1 (ET-1), which is known to activate protein kinase C can also mimic ischemic preconditioning. Isolated rabbit hearts experienced 30 min of regional ischemia followed by 120 min of reperfusion. Infarct size was measured with triphenyltetrazolium chloride. In control hearts infarction was 30.3 +/- 2.5% of the risk zone. Preconditioning with 5 min global ischemia and 10 min reperfusion reduced infarct size to 5.6 +/- 0.7% (P < 0.01). Perfusion with either 10 PM ET-1 at constant coronary artery flow for 5 min in lieu of ischemia or 50 PM ET-1 with 10 nM nicardipine to block the former's coronary constructive effect was quite protective and equipotent with preconditioning. Infarction averaged 7.2 +/- 0.8% and 5.8 +/- 1.7% of the risk zone, respectively. This protection could be blocked by PD 156 707 (10 microM), a highly specific endothelin receptor antagonist. Chelerythrine (5 microM), a PKC inhibitor, also aborted protection (22.0 +/- 1.7% infarction). However, 8-(p-sulfophenyl)theophylline (100 microM), an adenosine receptor blocker, given during ET-1 administration did not block ET-1's protective effect indicating that adenosine was not involved in the effect. PD 156707 failed to block the protection from ischemic preconditioning (12.6 +/- 2.3% infarction) revealing that endothelin is not an important physiological mediator of ischemic preconditioning. We conclude that ET-1 can mimic ischemic preconditioning in isolated rabbit hearts as would be predicted since its receptors are PKC-coupled, but that endogenous endothelin contributes little to ischemic preconditioning.
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PMID:Pretreatment with endothelin-1 mimics ischemic preconditioning against infarction in isolated rabbit heart. 901 41

We have previously reported that phosphorylation of adenylyl cyclase type VI (AC6) may result in the suppression of adenylyl cyclase activity during desensitization of the A2a-adenosine receptor-mediated cAMP response (A2a desensitization) in rat pheochromocytoma PC12 cells. In the present study, we demonstrate that protein kinase C (PKC) is responsible for the phosphorylation and inhibition of AC6 during A2a desensitization. Inhibition of PKC by several independent methods markedly blocked the suppression of AC6 during A2a desensitization. Purified PKC from rat brain directly phosphorylated and inhibited recombinant AC6 expressed in Sf21 cells. Substantially lower AC6 activities were also observed in PC12 cells overexpressing PKCdelta or PKCepsilon. Stimulation of A2a-R in PC12 cells under the same conditions as those required for A2a desensitization resulted in an increase in Ca2+-independent PKC activity. Most importantly, exogenous PKC did not further suppress AC6 activity in A2a-desensitized membranes. In vitro PKC phosphorylation of AC6 isolated from A2a-desensitized cells was also profoundly lower than that from control cells, suggesting a specific role for PKC in regulating AC6 during A2a desensitization in PC12 cells. Taken together, our data demonstrate that a calcium-independent, novel PKC inhibits AC6 activity during A2a desensitization in PC12 cells. Independent regulation of AC6 by calcium-independent PKC and by Ca2+ provides an exquisite mechanism for integrating signaling pathways to fine-tune cAMP synthesis.
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PMID:Protein kinase C inhibits adenylyl cyclase type VI activity during desensitization of the A2a-adenosine receptor-mediated cAMP response. 903 May 58


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