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 current study, we have characterized group I metabotropic glutamate (mGlu) receptor enhancement of 4-aminopyridine (4AP)-evoked [3H]glutamate release from rat cerebrocortical synaptosomes. The broad spectrum mGlu receptor agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD, 10 microM) increased 4AP-evoked [3H]glutamate release (143.32+/-2.73% control) only in the presence of exogenously applied arachidonic acid; an effect reversed by the inclusion of bovine serum albumin (BSA, fatty acid free). In contrast, the selective group I mGlu receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) potentiated (EC50 = 1.60+/-0.25 microM; Emax = 147.61+/-10.96% control) 4AP-evoked [3H]glutamate release, in the absence of arachidonic acid. This potentiation could be abolished by either the selective mGlu1 receptor antagonist (R,S)-1-aminoindan-1,5-dicarboxylic acid (AIDA, 1 mM) or the selective PKC inhibitor (Ro 31-8220, 10 microM) and was BSA-insensitive. The selective mGlu5 receptor agonist (R,S)-2-chloro-5-hydroxyphenylglycine (CHPG, 300 microM) was without effect. DHPG (100 microM) also potentiated both 30 mM and 50 mM K+ -evoked [3H]glutamate release (121.60+/-12.77% and 121.50 +/-4.45% control, respectively). DHPG (100 microM) failed to influence both 4AP-stimulated 45Ca2+ influx and 50 mM K+ -induced changes in synaptosomal membrane potential. Possible group I mGlu receptor suppression of tonic adenosine A1 receptor, group II/III mGlu receptors or GABA(B) receptor activity is unlikely since 4AP-evoked [3H]glutamate release was insensitive to the selective inhibitory receptor antagonists 8-cyclopentyl-1,3-dimethylxanthine, (R,S)-alpha-cyclopropyl-4-phosphonophenylglycine or CGP55845A, respectively. These data suggest an 'mGlu1 receptor-like' receptor potentiates [3H]glutamate release from cerebrocortical synaptosomes in the absence of exogenously applied arachidonic acid. This PKC dependent effect is unlikely to be via modulation of synaptosomal membrane potential or voltage-activated Ca2+ channels and not via a suppression of tonically active inhibitory adenosine A1 receptor, group II/III mGlu receptors or GABA(B) receptors.
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PMID:Group I mGlu receptors potentiate synaptosomal [3H]glutamate release independently of exogenously applied arachidonic acid. 1022 51

Leptin, the ob gene product that can decrease caloric intake and increase energy expenditure, is functionally released by insulin from adipose tissue. Adenosine is thought to be an important regulator of the action of insulin in adipose tissue. The present study investigated the role of adenosine in the release of leptin by insulin in isolated rat white adipocytes. Release of leptin, measured by radioimmunoassay, from insulin-stimulated samples was seen after 30 min. Adenosine deaminase, at concentrations sufficient to metabolize endogenous adenosine, decreased insulin-stimulated leptin release. Also, the insulin-stimulated leptin release was completely blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). Mediation of endogenous adenosine in this action of insulin was further supported by the assay of adenosine released into the medium from adipocytes stimulated with insulin. In addition, activation of adenosine A1 receptors by N6-cyclopentyladenosine (CPA) induced an increase in leptin release in a concentration-dependent manner that could be blocked by antagonists, either DPCPX or 8-(p-sulfophenyl)theophylline (8-SPT). In the presence of U73312, a specific inhibitor of phospholipase C (PLC), CPA-stimulated leptin secretion from adipocytes was reduced in a concentration-dependent manner, but it was not affected by U73343, the negative control for U73312. Moreover, chelerythrine and GF 109203X diminished the CPA-stimulated leptin secretion at concentrations sufficient to inhibit protein kinase C (PKC). These results suggest that, in isolated white adipocytes, the released adenosine acts as a helper and/or a positive regulator for insulin in the release of leptin via an activation of adenosine A1 receptors that involves the PLC-PKC pathway.
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PMID:Role of adenosine in insulin-stimulated release of leptin from isolated white adipocytes of Wistar rats. 1061 45

Adenosine is produced intracellularly during conditions of metabolic stress and is an endogenous agonist for four subtypes of G-protein linked receptors. Nucleoside transporters are membrane-bound carrier proteins that transfer adenosine, and other nucleosides, across biological membranes. We investigated whether adenosine receptor activation could modulate transporter-mediated adenosine efflux from metabolically stressed cells. DDT1 MF-2 smooth muscle cells were incubated with 10 microM [3H]adenine to label adenine nucleotide pools. Metabolic stress with the glycolytic inhibitor iodoacetic acid (1AA, 5 mM) increased tritium release by 63% (P < 0.01), relative to cells treated with buffer alone. The IAA-induced increase was blocked by the nucleoside transport inhibitor nitrobenzylthioinosine (1 microM), indicating that the increased tritium release was primarily a purine nucleoside. HPLC verified this to be [3H]adenosine. The adenosine A1 receptor selective agonist N6-cyclohexyladenosine (CHA, 300 nM) increased the release of [3H]purine nucleoside induced by IAA treatment by 39% (P < 0.05). This increase was blocked by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (10 microM). Treatment of cells with UTP (100 microM), histamine (100 microM), or phorbol-12-myristate-13-acetate (PMA, 10 microM) also increased [3H]purine nucleoside release. The protein kinase C inhibitor chelerythrine chloride (500 nM) inhibited the increase in [3H]purine nucleoside efflux induced by CHA or PMA treatment. The adenosine kinase activity of cells treated with CHA or PMA was found to be decreased significantly compared with buffer-treated cells. These data indicated that adenosine A1 receptor activation increased nucleoside efflux from metabolically stressed DDT1 MF-2 cells by a PKC-dependent inhibition of adenosine kinase activity.
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PMID:Stimulation of nucleoside efflux and inhibition of adenosine kinase by A1 adenosine receptor activation. 1066 Jan 14

Renal ischemic reperfusion (IR) injury is a significant clinical problem in anesthesia and surgery. Recently, it was demonstrated that both renal ischemic preconditioning (IPC) and systemic adenosine pretreatment protect against renal IR injury. In cardiac IPC, pertussis toxin-sensitive G-proteins (i.e., G(i/o)), protein kinase C (PKC), and ATP-sensitive potassium (K+(ATP)) channels are implicated in this protective signaling pathway. The aim of this study was to elucidate the signaling pathways that are responsible for renal protection mediated by both IPC and adenosine pretreatment. In addition, because A1 adenosine receptor antagonist failed to block renal IPC, whether activation of bradykinin, muscarinic, or opioid receptors can mimic renal IPC was tested because these receptors have been implicated in cardiac IPC. Rats were acutely pretreated with chelerythrine or glibenclamide, selective blockers of PKC and K+(ATP) channels, respectively, before IPC or adenosine pretreatment. Some rats were pretreated with pinacidil (K+(ATP)channel opener), bradykinin, methacholine, or morphine before renal ischemia. Twenty-four h later, plasma creatinine was measured. Separate groups of rats received pertussis toxin intraperitoneally 48 h before being subjected to the above protective protocols. IPC and adenosine pretreatment protected against renal IR injury. Pretreatment with pertussis toxin and chelerythrine abolished the protective effects of both renal IPC and adenosine. However, glibenclamide pretreatment had no effect on either renal IPC or adenosine-induced renal protection, indicating no apparent role for K+(ATP) channels. Moreover, pinacidil, bradykinin, methacholine, and morphine failed to protect renal function. Therefore, the conclusion is that cellular signal transduction pathways of renal IPC and adenosine pretreatment in vivo involve G(i/o) proteins and PKC but not K+(ATP) channels. Unlike cardiac IPC, bradykinin, muscarinic, and opioid receptors do not mediate renal IPC.
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PMID:Protein kinase C and G(i/o) proteins are involved in adenosine- and ischemic preconditioning-mediated renal protection. 1115 13

In an attempt to investigate the presence of adenosine A1 receptor in cell line, we used N6-cyclopentyladenosine (CPA), an agonist of adenosine A1 receptor, to incubate with C2C12 cells in vitro. CPA increased the uptake of radioactive glucose into C2C12 cells in a concentration-dependent manner and this action was abolished by the antagonists, both 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (1,3-dipropy1-8-cyclopentylxanthine) and 8-(p-sulfophenyl)theophylline (8-SPT), at concentrations sufficient to block adenosine A1 receptor. Northern blot analysis showed the expression of adenosine A1 receptor mRNA by C2C12 cells. Western blotting also indicated a positive correlation (r = 0.99) of antibody recognized adenosine A1 receptor with membrane protein. The presence of adenosine A1 receptor in C2C12 cells can thus be considered. In the presence of U73312 (1-[6[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1H- pyrrole-2,5-dione), the specific inhibitor of phospholipase C, glucose uptake stimulated by CPA into C2C12 cells was reduced concentration-dependently while it was not modified by U73343 (1-[6[[(17 beta)-3-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-2,5- pyrrolidinedione), the negative control of U73312. Moreover, chelerythrine and GF 109203X (3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4-(1H-indol-3- yl)-1H-pyrrole-2,5-dione) also diminished the CPA-stimulated glucose uptake at concentrations sufficient to inhibit protein kinase C. The obtained data suggest that activation of adenosine A1 receptor in C2C12 cells may increase the glucose uptake via phospholipase C-protein kinase C pathway.
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PMID:Characterization of adenosine A1 receptor in cultured myoblast C2C12 cells of mice. 1127 Jan 41

We investigated the mechanisms responsible for the anti-lipolytic effect of intracellular Ca2+ ([Ca2+]i) in human adipocytes. Increasing [Ca2+]i inhibited lipolysis induced by b-adrenergic receptor activation, A1 adenosine receptor inhibition, adenylate cyclase activation, and phosphodiesterase (PDE) inhibition, as well as by a hydrolyzable cAMP analog, but not by a nonhydrolyzable cAMP analog. This finding indicates that the anti-lipolytic effect of [Ca2+]i may be mediated by the activation of adipocyte PDE. Consistent with this theory, [Ca2+]i inhibition of isoproterenol-stimulated lipolysis was reversed completely by the nonselective PDE inhibitor isobutyl methylxanthine and also by the selective PDE 3B inhibitor cilostamide, but not by selective PDE 1 and 4 inhibitors. In addition, phosphatidylinositol-3 kinase inhibition with wortmannin completely prevented insulin's anti-lipolytic effect but only minimally blocked [Ca2+]i's effect, which suggests that [Ca2+]i and insulin may activate PDE 3B via different mechanisms. In contrast, the antilipolytic effect of [Ca2+]i was not affected by inhibitors of calmodulin, Ca2+/calmodulin-dependent kinase, protein phosphatase 2B, and protein kinase C. Finally, [Ca2+]i inhibited significantly isoproterenol-stimulated increases in cAMP levels and hormone-sensitive lipase phosphorylation in human adipocytes. In conclusion, increasing [Ca2+]i exerts an antilipolytic effect mainly by activation of PDE, leading to a decrease in cAMP and HSL phosphorylation and, consequently, inhibition of lipolysis.
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PMID:Mechanism of intracellular calcium ([Ca2+]i) inhibition of lipolysis in human adipocytes. 1164 Dec 62

Adenosine activates a signal transduction pathway (STP) in the heart and the brain, conferring protection against ischemia-reperfusion insult. Activation of protein kinase C (PKC), probably mainly PKC-epsilon, has been demonstrated to be part of the heart STP, but its role in the neuronal pathway is less clear. Here, we provide proof for the participation of PKC-epsilon in the neuronal adenosine-activated STP. Primary rat neuronal cultures were exposed to chemical ischemia by iodoacetate, followed by reperfusion. The cultured neurons were protected against this insult by activation of the adenosine mechanism, by N6-(R)-phenylisopropyladenosine [R(-)-PIA], a specific A1 adenosine receptor agonist. Exposure of the cultures to bisindolylmaleimide I, a highly selective PKC inhibitor, abrogated the protection. The exposure of the cultures to R(-)-PIA was found to result in phosphorylation (activation) of PKC-epsilon. Furthermore, insertion into the cells of a specific peptide inhibitor of PKC-epsilon translocation (epsilonV1-2), also abrogated the protection conferred by R(-)-PIA. These results demonstrate that activation of PKC-epsilon is a vital step in the neuronal adenosine-activated STP.
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PMID:Protein kinase C-epsilon is involved in the adenosine-activated signal transduction pathway conferring protection against ischemia-reperfusion injury in primary rat neuronal cultures. 1255 3

This study examined the hypothesis that the activation of A1 adenosine receptor (A1AR) induces delayed cellular protection (DCP) in porcine coronary smooth muscle cells (PCSMC). The following groups of cultured PCSMC, subjected to simulated ischemia (SI) at 20 h were studied: (a) SI: with ischemia alone; (b) A1AR agonist chloro-N6-cyclopentyl adenosine (CCPA: CCPA (1 microM) alone; (c) CCPA + PKC inhibitor chelerythrine chloride (CCL): CCPA and 1 microM CCL; (d) CCPA + iNOS inhibitor S-methylthiourea (SMT): CCPA and 100 nM SMT; (e) CCPA + KATP channel blocker Glibenclamide (Glb): CCPA and 50 microM Glb; (f) CCPA + mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD): CCPA and 100 microM of 5-HD; (g) CCPA + A1AR antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX): CCPA and 1 microM DPCPX. The release of LDH into the medium as well as the amount of LDH remaining in the cells was used as a marker of cellular injury and cell viability. Up-regulation of A1AR, epsilon-PKC, iNOS and HSP 72i was detected through Westem blot analysis. The cellular resistance (%LDH remaining in the cells) acquired by PCSMC due to CCPA (59.42 +/- 1.57) was significantly blocked by CCL: 39.30 +/- 2.03; SMT: 41.37 +/- 1.98; Glb: 47.24 +/- 1.31; 5-HD: 47.69 +/- 1.40 and DPCPX: 42.92 +/- 0.79. CCPA increased the expression of A1AR (1.30 fold), epsilon-PKC (1.20 fold), iNOS (1.50 fold), and HSP 72i (1.70 fold) compared to the controls. CCPA-induced up-regulation of A1AR, epsilon-PKC, iNOS, HSP 72i, and the opening of both mitochondrial and sarcolemmal KATP channels may possibly participate in signaling cascade. Our study suggests that A1AR activation up-regulates iNOS, HSP 72i via epsilon-PKC signaling pathway to activate both mitochondrial and sarcolemmal KATP channels for cellular protection against SI in the cultured PCSMC.
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PMID:Mechanisms of delayed preconditioning with A1 adenosine receptor activation in porcine coronary smooth muscle cells. 1259 31

We have previously reported that prolonged exposure of porcine coronary arteries to adenosine agonists upregulates protein kinase C (PKC) through the activation of adenosine A1 receptor-coupled to pertussis toxin sensitive G-protein(s) [Am. J. Physiol. 264 (1993) H1465; Am. J. Physiol. 269 (1995) H1619]. The mechanism(s) by which A1 adenosine receptor upregulates PKC (isoforms) are not yet clearly understood. In the present study, we identified the alpha, beta 1, beta 2, gamma, epsilon, and zeta PKC isoforms that were upregulated by adenosine A1 receptor agonist as a possible mechanism(s) involved for this upregulation. Incubation of porcine coronary smooth muscle cells (PCSMC) with adenosine A1 receptor agonist (2s)-N6-[2-endo-norbornyl]adenosine (ENBA) caused an upregulation of PKC (isoforms), which were blocked by adenosine A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). Western blot analysis using specific antibodies to PKC isoforms indicated that all the isoforms tested (alpha, beta I, beta II, mu, gamma, delta, epsilon, and zeta) were present in the primary cultured smooth muscle cells from porcine coronary artery. Western blot studies indicated that PKC alpha, beta I, beta II, gamma, epsilon, and zeta isoforms were upregulated in a dose dependent manner by adenosine agonist (ENBA) and PKC delta and mu were not altered.
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PMID:Protein kinase C isoforms and A1 adenosine receptors in porcine coronary smooth muscle cells. 1261 90

To date, there are two pathways discussed as a mechanism of ischemic preconditioning. Activation of protein kinase C by ischemic preconditioning increases adenosine release. The increased adenosine further activates protein kinase C through adenosine A1 receptors, and activated protein kinase C induces an infarct size-reducing effect through the opening of K(ATP) channels (pathway I). Meanwhile, activation of the alpha1b-adrenoceptor through increased interstitial noradrenaline by ischemic preconditioning is also associated with the ischemic preconditioning effect. However, the exact pathway of this is unknown, although it is postulated that protein kinase C and adenosine are cross-talking. Myocardial interstitial noradrenaline levels were measured in Japanese white rabbits using a microdialysis technique. Ischemic preconditioning was elicited by a single episode of 5 min ischemia and 5 min reperfusion. The infarct size was measured in rabbits subjected to 30 min ischemia and 48 h reperfusion. An increase in interstitial noradrenaline by ischemic preconditioning was not inhibited by an adenosine A1 receptor blocker (1,3-dipropyl-8-cyclopentylxanthine), but was inhibited by an adenosine A2 receptor blocker (3,7-dimethyl-1-(2-propynyl) xanthine) or protein kinase C inhibitors (staurosporine and polymyxin B). Interstitial noradrenaline was increased by an adenosine A2 receptor agonist (CGS21680) and the increase was inhibited by a protein kinase C inhibitor. The infarct size-reducing effect of ischemic preconditioning was inhibited by a selective alpha1b-adrenoceptor blocker (chloroethylclonidine) or a protein kinase C inhibitor, and that of tyramine, an inducer of noradrenaline, was inhibited by protein kinase C inhibitor. This suggests the presence of pathway II, indicating ischemic preconditioning --> activation of protein kinase C --> adenosine release --> pre-synaptic adenosine A2 receptors --> activation of protein kinase C in sympathetic nerve --> noradrenaline --> alpha1b-adrenoceptor --> activation of protein kinase C in myocytes --> infarct size-reducing effect. In addition, the ischemic preconditioning effect on infarct size was not inhibited by 1,3-dipropyl-8-cyclopentylxanthine, but was inhibited by 3,7-dimethyl-1-(2-propynyl) xanthine or chloroethylclonidine, suggesting the greater importance of pathway II compared with pathway I. Thus, pathway II plays an important role in the pathogenesis of the infarct size-reducing effect in ischemic preconditioning.
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PMID:Cross-talk among noradrenaline, adenosine and protein kinase C in the mechanisms of ischemic preconditioning in rabbits. 1268 95


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