EC:2.7.11.13 - FACTA Search

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)

In the prostatic portion of rat vas deferens, the non-selective adenosine receptor agonist NECA (0.1-30 microM), but not the A(2A) agonist CGS 21680 (0.001-10 microM), caused a facilitation of electrically evoked noradrenaline release (up to 43 +/- 4%), when inhibitory adenosine A(1) receptors were blocked. NECA-elicited facilitation of noradrenaline release was prevented by the A(2B) receptor-antagonist MRS 1754, enhanced by preventing cyclic-AMP degradation with rolipram, abolished by the protein kinase A inhibitors H-89, KT 5720 and cyclic-AMPS-Rp and attenuated by the protein kinase C inhibitors Ro 32-0432 and calphostin C. The adenosine uptake inhibitor NBTI also elicited a facilitation of noradrenaline release; an effect that was abolished by adenosine deaminase and attenuated by MRS 1754, by inhibitors of the extracellular nucleotide metabolism and by blockade of alpha(1)-adrenoceptors and P2X receptors with prazosin and NF023, respectively. It was concluded that adenosine A(2B) receptors are involved in a facilitation of noradrenaline release in the prostatic portion of rat vas deferens that can be activated by adenosine formed by extracellular catabolism of nucleotides. The receptors seem to be coupled to the adenylyl cyclase-protein kinase A pathway but activation of the protein kinase C by protein kinase A, may also contribute to the adenosine A(2B) receptor-mediated facilitation of noradrenaline release.
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PMID:Coupling to protein kinases A and C of adenosine A2B receptors involved in the facilitation of noradrenaline release in the prostatic portion of rat vas deferens. 1522

The early phase of preconditioning (PC) lasts 2 to 3 hours and protects against myocardial infarction, but not against stunning. In contrast, the late phase of PC lasts for 3 to 4 days and protects against both myocardial stunning and infarction, making this phenomenon more clinically relevant. Late PC is a genetic reprogramming of the heart that involves the activation of several stress-responsive genes, which ultimately results in the development of a cardioprotective phenotype. Sublethal ischemic insults release chemical signals (nitric oxide [NO], adenosine, and reactive oxygen species) that trigger a series of signaling events (eg, activation of protein kinase C, Src protein tyrosine kinases, Janus kinases 1/2, and nuclear factor-kappaB) and culminates in increased synthesis of inducible NO synthase, cyclooxygenase-2, heme oxygenase-1, aldose reductase, Mn superoxide dismutase, and probably other cardioprotective proteins. In addition to ischemia, heat stress, exercise, and cytokines can also induce a similar series of events. Perhaps most importantly, many pharmacologic agents (eg, NO donors, adenosine receptor agonists, endotoxin derivatives, or opioid receptor agonists) can mimic the effects of ischemia in inducing the late phase of PC, suggesting that this phenomenon might be exploited therapeutically. The purpose of this review is to summarize the mechanisms that underlie the late phase of ischemic PC.
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PMID:Delayed adaptation of the heart to stress: late preconditioning. 1545 41

Adenosine binds to a class of G-protein coupled receptors, which are further distinguished as A(1), A(2a), A(2b) and A(3) adenosine receptors. As we have shown earlier, the stable adenosine analogue NECA (N6-(R)-phenylisopropyladenosine) stimulates IL-6 expression in the human astrocytoma cell line U373 MG via the A(2b) receptor. The mechanism by which NECA promotes astrocytic IL-6 expression has not been identified. By using various inhibitors of signal transduction, we found that p38 mitogen-activated protein kinases (MAPK) activation (inhibitor SB202190), but not extracellular signal-regulated kinase (ERK) (PD98059) and c-jun N-terminal kinase (JNK)(SP600125), is essential in the NECA-induced signalling cascade that leads to the increase in IL-6 synthesis in U373 MG cells. Results obtained with protein kinase C (PKC) inhibitors that have different substrate specificities, indicated that the PKC delta and epsilon isoforms are also involved in adenosine receptor A(2b) dependent upregulation of IL-6 expression. This is supported by the fact that NECA induced the activation of PKC delta and epsilon in U373 MG cells.
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PMID:IL-6 expression induced by adenosine A2b receptor stimulation in U373 MG cells depends on p38 mitogen activated kinase and protein kinase C. 1576 52

Adenosine kinase phosphorylates adenosine to AMP, the primary pathway for adenosine metabolism under basal conditions. Inhibition of adenosine kinase results in a site-specific increase in interstitial adenosine. Using a rat model of myocardial infarction, we examined the protective effects of adenosine kinase inhibition. Male Sprague-Dawley rats underwent 30 min regional occlusion followed by 90 min reperfusion. Infarct size, expressed as a percent of the area-at-risk, IS/AAR(%), was 58.0 +/- 2.1 % in untreated rats. Pretreatment with the adenosine kinase inhibitor, 5-iodotubercidin (1 mg/kg), limited infarct development to 37.5+/-3.7% (P < 0.001). The A(1) adenosine receptor (A(1)AR) antagonist, DPCPX (100 microg/kg), abolished the infarct-sparing effect of 5-iodotubercidin (IS, 62.8 +/- 1.3%). Similarly, the A(3) adenosine receptor (A(3)AR) antagonist, MRS-1523 (2 mg/kg), and the delta-opioid receptor (DOR) antagonist, BNTX, (1 mg/kg) abolished the reduction of IS produced by iodotubercidin. Pretreatment with the ROS scavenger, 2-MPG (20 mg/kg), or the PKC-delta antagonist, rottlerin (0.3 mg/kg) also abolished iodotubercidin-mediated cardioprotection. Furthermore, pretreatment with 5-HD, a mitochondrial K(ATP) (mitoK(ATP)) channel inhibitor, but not the sarcolemmal K(ATP) channel blocker, HMR-1098, abrogated the beneficial effects of adenosine kinase inhibition (IS, 59.5 +/- 3.8%). These data suggest that inhibition of adenosine kinase is effective in reducing infarct development via A(1)AR, A(3)AR and DOR activation. Data also suggest that this protection is mediated via ROS, PKC-delta and mitoK(ATP) channels.
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PMID:Cardioprotection following adenosine kinase inhibition in rat hearts. 1579 95

Brief periods of ischemia and reperfusion are able to protect the heart from irreversible injury induced by consequent prolonged ischemia and reperfusion stress. This phenomenon called ischemic preconditioning (IP) may limit infarct size, enhance postischemic recovery of cardiac function, reduce reperfusion arrhythmias and vascular dysfunction. Mechanisms of IP are tightly related to alterations of efficiency of metabolic pathways and maintenance of ion homeostasis in ischemic cardiac myocytes. They may be initiated by formation of various triggers (adenosine, bradykinin, NO, free oxygen radicals etc.) that interact with receptors of cardiomyocytes and vascular endothelium or directly alter activity of enzymes. These interactions lead to activation of different pathways of intracellular signal conduction involving contribution of mediators and complex of the secondary messengers of IP. The most typical of them are e-isoform of protein kinase C and the ATP-dependent potassium channels. Biochemical pathways of molecular signaling in the preconditioned myocardium may be different, but always have same final effectors -- intracellular metabolism and ion homeostasis. As a rule, successfully preconditioned myocardium exhibits improved energy state of ischemic cardiomyocytes, reduced Ca(+) overload and attenuated damage of the sarcolemma and mitochondrial membranes. These beneficial changes provide myocardial salvage under conditions of deficient supply of cardiomyocytes with energy substrates and oxygen. Stimulation of adaptative mechanisms of IP is possible with specific receptor agonists or activation of secondary messenger pathways without causing ischemia. At present study of such pharmacological approaches to treating ischemia is a high priority task. In clinical practice selective openers of ATP-dependent potassium channels, A(1) and A(2) adenosine receptor agonists and Na(+)/H(+) exchange inhibitors are used to affect the final effectors of signaling pathways. These pharmacological agents are explored in transluminal coronary angioplasty, cardiac surgery and organ transplantation.
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PMID:[Ischemic preconditioning: from theory to practice]. 1623 96

Reactive oxygen species (ROS)-mediated signaling is implicated in early ischemic preconditioning (PC). A NOX-2-containing NADPH oxidase is a recognized major source of ROS in cardiac myocytes, whose activity is augmented by preconditioning mimetics, such as angiotensin II. We hypothesized that this oxidase is an essential source of ROS in PC. Hearts from wild-type (WT) and NOX-2 knockout (KO) mice were Langendorff perfused and subjected to 35 min ischemia/reperfusion with or without preceding PC or drug treatment. Infarct size was measured by triphenyl tetrazolium chloride staining, and NADPH oxidase activity by lucigenin chemiluminescence. PC significantly attenuated infarct size in WT (26+/-2% vs. control, 38+/-2%, P<0.05) yet was ineffective in KO hearts (33+/-3% vs. control, 34+/-3%). Concomitantly, PC significantly increased NADPH oxidase activity in WT (+41+/-13%; P<0.05), but not in KO (-5+/-18%, P=NS). The ROS scavenger MPG (N-2-mercaptopropionyl glycine, 300 micromol/L) abrogated PC in WT (39+/-2% vs. control, 33+/-1%). CCPA (2-chloro N6 cyclopentyl adenosine, 200 nmol/L), a putative ROS-independent PC trigger, significantly attenuated infarct size in WT, MPG-treated WT and KO hearts (24+/-2, 23+/-1, and 20+/-3%, respectively, P<0.05). Furthermore, CCPA did not augment NADPH oxidase activity over control (+22+/-11%, P=NS). Inhibition of protein kinase C (PKC) with chelerythrine (CHE, 2 micromol/L) completely abrogated both PC (38+/-2% vs. CHE alone, 35+/-2%) and associated increases in oxidase activity (+3+/-10%, P=NS). PKC-dependent activation of a NOX-2-containing NADPH oxidase is pivotally involved in early ischemic PC. However, adenosine receptor activation can trigger a ROS and NOX-2 independent PC pathway.
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PMID:Pivotal role of NOX-2-containing NADPH oxidase in early ischemic preconditioning. 1623 99

We tested the hypothesis that ATP is an enteric neurotransmitter that acts at P2Y1 excitatory purinergic receptors on intestinal secretomotor neurons to evoke neurogenic mucosal secretion in the guinea pig. Ussing chamber methods for studying neurogenic intestinal secretion were used to test the hypothesis. Application of ATP evoked concentration-dependent increases in short circuit current (Isc) indicative of stimulation of electrolyte secretion. MRS2179, a selective P2Y1 purinergic receptor antagonist, suppressed the ATP-evoked responses in a concentration-dependent manner with an IC50 of 0.9+/-0.1 microM. Tetrodotoxin or a selective vasoactive intestinal peptide (VPAC1) receptor antagonist suppressed or abolished the ATP-evoked responses. A selective VPAC1 receptor antagonist also suppressed Isc responses evoked by electrical field stimulation of the secretomotor neurons. Secretory responses to ATP were not suppressed by scopolamine, piroxicam nor selective adenosine receptor antagonists. Region-specific differences in responses to ATP corresponded to regional differences in the expression of mRNA transcripts for the P2Y1 receptor. Post-receptor signal transduction for the P2Y1-evoked responses involved stimulation of phospholipase C and an IP3/Ca2+-calmodulin/protein kinase C signaling cascade. Our evidence suggests that ATP is released as a neurotransmitter to stimulate neurogenic mucosal secretion by binding to P2Y1 receptors expressed by VIP-ergic secretomotor neurons.
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PMID:Neurogenic secretion mediated by the purinergic P2Y1 receptor in guinea-pig small intestine. 1656 16

We have already reported that A(3) adenosine receptor stimulation reduces [(3)H]-ryanodine binding and sarcoplasmic reticulum Ca(2+) release in rat heart. In the present work we have investigated the transduction pathway responsible for this effect. Isolated rat hearts were perfused for 20 min in the presence of the following substances: 100 nM N(6)-(iodobenzyl)-adenosine-5'-N-methyluronamide (IB-MECA), an A(3) adenosine agonist; 10 muM U-73122, a phospholipase C inhibitor; 2 muM chelerythrine, a protein kinase C inhibitor. At the end of perfusion, the hearts were homogenized and [(3)H]-ryanodine binding was assayed. IB-MECA produced a significant decrease in ryanodine binding, which was abolished in the presence of chelerythrine but not in the presence of U-73122. RT-PCR experiments showed that ryanodine receptor gene expression was not affected by IB-MECA. In Western blot experiments, ryanodine receptor phosphorylation on serine 2809 was not modified after perfusion with IB-MECA. We conclude that modulation of SR Ca(2+) release channel by IB-MECA is dependent on protein kinase C activation. However, in this model protein kinase C activation is not due to phospholipase C activation. In addition, changes in ryanodine receptor gene expression or direct phosphorylation of the ryanodine receptor on serine 2809 residue do not appear to occur.
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PMID:Modulation of cardiac sarcoplasmic reticulum calcium release by aenosine: a protein kinase C- dependent pathway. 1658 39

Blockage of the p53 tumor suppressor has been found to impair nerve growth factor (NGF)-induced neurite outgrowth in PC-12 cells. We report herein that such impairment could be rescued by stimulation of the A(2A) adenosine receptor (A(2A)-R), a G protein-coupled receptor implicated in neuronal plasticity. The A(2A)-R-mediated rescue occurred in the presence of protein kinase C (PKC) inhibitors or protein kinase A (PKA) inhibitors and in a PKA-deficient PC-12 variant. Thus, neither PKA nor PKC was involved. In contrast, expression of a truncated A(2A)-R mutant harboring the seventh transmembrane domain and its C terminus reduced the rescue effect of A(2A)-R. Using the cytoplasmic tail of the A(2A)-R as bait, a novel-A(2A)-R-interacting protein [translin-associated protein X (TRAX)] was identified in a yeast two-hybrid screen. The authenticity of this interaction was verified by pull-down experiments, coimmunoprecipitation, and colocalization of these two molecules in the brain. It is noteworthy that reduction of TRAX using an antisense construct suppressed the rescue effect of A(2A)-R, whereas overexpression of TRAX alone caused the same rescue effect as did A(2A)-R activation. Results of [(3)H]thymidine and bromodeoxyuridine incorporation suggested that A(2A)-R stimulation inhibited cell proliferation in a TRAX-dependent manner. Because the antimitotic activity is crucial for NGF function, the A(2A)-R might exert its rescue effect through a TRAX-mediated antiproliferative signal. This antimitotic activity of the A(2A)-R also enables a mitogenic factor (epidermal growth factor) to induce neurite outgrowth. We demonstrate that the A(2A)-R modulates the differentiation ability of trophic factors through a novel interacting protein, TRAX.
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PMID:Rescue of p53 blockage by the A(2A) adenosine receptor via a novel interacting protein, translin-associated protein X. 1670 26

Human mast cells express functional A(2A) and A(2B) adenosine receptors. However, only stimulation of A(2B), not A(2A), leads to secretion of interleukin (IL)-4, an important step in adenosine receptor-mediated induction of IgE synthesis by B-cells. In this study, we investigate intracellular pathways that link stimulation of A(2B) receptors to IL-4 up-regulation in HMC-1 mast cells. Both A(2A) and A(2B) receptors couple to G(s) proteins and stimulate adenylate cyclase, but only A(2B) stimulates phospholipase Cbeta through coupling to G(q) proteins leading to activation of protein kinase C and calcium mobilization. Inhibition of phospholipase Cbeta completely blocked A(2B) receptor-dependent IL-4 secretion. The protein kinase C inhibitor 2-{8-[(dimethylamino)-methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methyl-1H-indol-3-yl)maleimide (Ro-32-0432) had no effect on A(2B) receptor-mediated IL-4 secretion but inhibited phorbol 12-myristate 13-acetate-stimulated IL-4 secretion. In contrast, chelation of intracellular Ca(2+) inhibited both A(2B) receptor- and ionomycin-dependent IL-4 secretion. This Ca(2+)-sensitive pathway probably includes calcineurin and nuclear factor of activated T cells, because A(2B) receptor-dependent IL-4 secretion was blocked with cyclosporin A or 11R-VIVIT peptide. G(s)-linked pathways also play a role in the A(2B) receptor-dependent stimulation of IL-4 secretion; inhibition of adenylate cyclase or protein kinase A attenuated A(2B) receptor-dependent IL-4 secretion. Although stimulation of adenylate cyclase with forskolin did not increase IL-4 secretion on its own, it potentiated the effect of Pasteurella multocida toxin by 2-fold and ionomycin by 3-fold. Both forskolin and stimulation of A(2B) receptors up-regulated NFATc1 protein levels. We conclude that A(2B) receptors up-regulate IL-4 through G(q) signaling that is potentiated via cross-talk with G(s)-coupled pathways.
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PMID:Cross-talk between G(s)- and G(q)-coupled pathways in regulation of interleukin-4 by A(2B) adenosine receptors in human mast cells. 1670 27

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