Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenosine modulates generation of superoxide anion by neutrophils via occupancy of specific adenosine A2A receptors. However, the intracellular signal transduction pathways by which occupancy of neutrophil adenosine A2A receptors inhibits superoxide anion generation (O2.-) are not well understood. We, therefore, tested the hypothesis that signaling at polymorphonuclear leukocyte (PMN) adenosine receptors proceeds via activation of a serine/threonine protein phosphatase (pp). Both the specific pp1 inhibitor calyculin A (10 nM) and the pp2A inhibitor okadaic acid (10 microM) enhanced O2.- generation (185 +/- 24 and 189 +/- 35% of control, respectively, p < 0.0001 for both, n = 8), as reported previously. Calyculin A, but not okadaic acid, completely reversed inhibition of stimulated O2.- generation by the adenosine A2 receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA; IC50 = 30 nM; p < 0.0001, analysis of variance). Calyculin A also reversed the adenosine receptor-mediated desensitization of bound chemoattractant receptors in neutrophils. Treatment of PMNs with NECA increased the pp1 activity of crude membrane preparations in a time- and dose-dependent fashion (EC50 = 40 nM; p < 0.001, analysis of variance, n = 5). NECA inhibited cytosolic protein phosphatase activity by 78 +/- 12% (p < 0.003, n = 6) but did not shift pp1 catalytic subunit from cytosol to plasma membrane. Similar changes were observed in neutrophil cytoplasts depleted of organelles and nucleus. Moreover, the selective protein kinase A inhibitor KT5720 (10 microM) reversed the capacity of dibutyryl cAMP but not NECA to increase pp1 activity (p < 0.01, n = 5) in keeping with its effects on O2.- generation. Western blot analysis of PMN subcellular fractions demonstrated the presence of pp1alpha and pp1gamma1 but not pp1gamma2 isotypes in both cytosol and plasma membrane but not in azurophil or specific granules. We conclude from these studies that signal transduction by adenosine in PMN proceeds via a novel pathway: cAMP-independent activation of a serine/threonine protein phosphatase in the plasma membrane.
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PMID:Adenosine A2 receptor occupancy regulates stimulated neutrophil function via activation of a serine/threonine protein phosphatase. 866 42

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

Using the reverse transcription polymerase chain reaction (RT-PCR) we found that human neutrophils express mRNA for both A2A and A2B adenosine receptors, and using selective adenosine receptor agonists and antagonists we have characterized the type of adenosine receptor mediating inhibition of formyl-Met-Leu-Phe (fMLP)-induced oxidative burst. The order of potency of agonists was 5'-N-ethyl-carboxamidoadenosine (NECA) > 2-phenylaminoadenosine > 2-[p-(2-carbonyl-ethyl)-phenyl-ethylamino]-5'-N-ethyl-carboxamido adenosine (CGS 21680) > adenosine > N6-cyclopentyl-adenosine. This agrees with the agonist potency at human A2A receptors. The effect of adenosine was antagonized by 30 microM theophylline > caffeine = paraxanthine, i.e. concentrations close to those occurring in plasma after consumption of caffeine-containing beverages. The effect of NECA was unaltered by the A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine, but inhibited by the A2A receptor selective antagonists 4-amino-8-chloro-1-phenyl-[1,2,4]-triazolo[4,3-a]quinoxaline (CP 66,713), 1,3-dipropyl-8-(3,4-dimethoxystyryl) -7-methylxanthine (KF 17387) and 8-(3-chlorostyryl)caffeine as well as by the non-selective, non-xanthine antagonist 5-amino-9-chloro-2-(2-furyl)-[1,2,4]-triazolo-[1,5-c]quinazoline methane sulphonate (CGS 15943). The adenosine receptor mediated responses were antagonized by the protein kinase A blocker Rp-cyclic adenosine 3',5'-phosphorothioate (Rp-cAMP). In conclusion, the adenosine-induced inhibition of neutrophil activation is mediated by adenosine A2A receptors.
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PMID:Adenosine A2A receptors mediate the inhibitory effect of adenosine on formyl-Met-Leu-Phe-stimulated respiratory burst in neutrophil leucocytes. 887 55

The role of the intracellular second messengers guanosine 3', 5'-cyclic monophosphate (cGMP) and adenosine 3', 5'-cyclic monophosphate (cAMP) in the control of macromolecule permeability was studied in cultured monolayers of microvascular coronary endothelial cells from rat. Macromolecule permeability was determined as passage of fluorescein isothiocyanate (FITC)-labeled albumin across the monolayers. Activation of adenylyl cyclase by the beta-adrenoceptor agonist isoproterenol (Iso; 10(-5) M) and the A2-adenosine receptor agonist 5'-(N-ethylcarboxamido)-adenosine (NECA; 10(-7) M) induced an increase in cellular cAMP contents that was accompanied by an increase in albumin flux. Effects of Iso and NECA on cellular cAMP level and albumin flux could be antagonized by a stimulator of the particular guanylyl cyclase, atrial natriuretic peptide (ANP; 10(-7) M), and stimulators of the soluble guanylyl cyclase, 3-morpholinosydnonimine (SIN-1; 10(-7) M) and sodium nitroprusside (SNP; 10(-6) M). ANP, SIN-1, and SNP also reduced cAMP content and basal macromolecule flux in unstimulated monolayers. 8-Bromoguanosine 3', 5'-cyclic monophosphate (8-BrcGMP; 5 x 10(-6) M), a stimulator of protein kinase G, reduced the increase in albumin flux under Iso (10(-5) M), NECA (10(-7) M), or 8-bromoadenosine 3', 5'-cyclic monophosphate (8-BrcAMP; 5 x 10(-6) M). The present study shows that cGMP and cAMP are functional antagonists in the control of macro molecule permeability.
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PMID:Functional antagonism between cAMP and cGMP on permeability of coronary endothelial monolayers. 896 65

PC12 cells are known to express A2A adenosine receptors that are linked to adenylyl cyclase. We investigated the role played by A2A adenosine receptors in the expression of the rat tyrosine hydroxylase (TH) gene in PC12 cells. The A2A selective adenosine receptor agonist 2-(p-2-carboxyethyl)phenylethylamino)-5'-N-ethylcarboxyamidoade nosine (CGS21680) caused TH mRNA levels to increase to more than twice the level of the untreated control. Transient transfection analysis demonstrated that the transcription of the TH gene was markedly enhanced upon treatment with CGS21680. The adenosine receptor-mediated TH gene expression was confirmed by the inhibitory effects that adenosine receptor antagonists had on the CGS21680 response. Mutational analysis of the 5' upstream region of the TH gene revealed that the cAMP response element (CRE) at -45 to -38 bp was responsible for the CGS21680 effect. Gel mobility shift assays revealed that six CRE-specific DNA-protein complexes were formed, and the amounts of three of them were significantly increased by treatment with CGS21680. Co-transfection with an expression vector containing protein kinase A (PKA) inhibitor markedly decreased the CGS21680 effect. The results suggest that stimulation of the A2A adenosine receptor leads to an elevated expression of the TH gene by changing the binding pattern of DNA binding proteins that interact with CRE through activation of protein kinase A.
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PMID:Stimulation of the A2A adenosine receptor increases expression of the tyrosine hydroxylase gene. 903 Jun 95

We investigated adenosine stimulation of DNA synthesis in human endothelial cells by measuring [3H]thymidine incorporation in cultures derived from human umbilical veins. After 18 h of exposure to adenosine in serum-free medium, endothelial cell [3H]thymidine incorporation was increased by 30-64%. Adenosine-induced DNA synthesis was not mimicked by adenosine receptor agonists and was not inhibited by adenosine receptor antagonists. Adenosine-induced DNA synthesis was inhibited 81% by 100 microM 5'-(N,N-dimethyl)amiloride, an inhibitor of Na+/H+ exchange, and was totally inhibited by 10 microM 2',4'-dibromoacetophenone, an inhibitor of phospholipase A2 (PLA2). Adenosine increased adenosine 3',5'-cyclic monophosphate levels in endothelial cells, but adenosine-induced DNA synthesis was not inhibited by the protein kinase A (PKA) inhibitor Rp-cAMPS. Both ATP and the phorbol ester 4beta-phorbol 12-myristate 13-acetate (PMA) increased DNA synthesis in human endothelial cells. Stimulation by ATP was inhibited by the P2-receptor antagonist suramin, and PMA stimulation was inhibited by the protein kinase C (PKC) inhibitor H-7. Neither suramin nor H-7 inhibited adenosine-stimulated DNA synthesis. The results suggest that Na+/H+ exchange and PLA2 are involved in adenosine-induced DNA synthesis in cultures of human endothelial cells independently of adenosine receptor, PKA, or PKC activation.
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PMID:Adenosine stimulation of DNA synthesis in human endothelial cells. 908 26

The regulatory role of A2A adenosine receptors in P2 purinoceptor-mediated calcium signaling was investigated in rat pheochromocytoma (PC12) cells. When PC12 cells were treated with 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS-21680), a specific agonist of the A2A adenosine receptor, the extracellular ATP-evoked rise in cytosolic free Ca2+ concentration ([Ca2+]i) was inhibited by 20%. Both intracellular calcium release and inositol 1,4,5-trisphosphate production evoked by ATP were not affected by CGS-21680 treatment. However, ATP-evoked Ca2+ influx was inhibited following CGS-21680 stimulation. The CGS-21680-mediated inhibition occurred independently of nifedipine-induced inhibition of the [Ca2+]i rise. The CGS-21680-induced inhibition was completely blocked by reactive blue 2. The CGS-21680 effect was mimicked by forskolin and dibutyryl-cyclic AMP and blocked by Rp-adenosine 3',5'-cyclic monophosphothioate, a protein kinase A inhibitor, or by staurosporine, a general kinase inhibitor. The data suggest that in PC12 cells activation of A2A adenosine receptors leads to inhibition of P2 purinoceptor-mediated Ca2+ influx through ATP-gated cation channels and involves protein kinase A.
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PMID:A2A adenosine receptors inhibit ATP-induced Ca2+ influx in PC12 cells by involving protein kinase A. 910 46

1. The modulation by adenosine of GABA-activated current (IGADA) was studied in freshly isolated rat dorsal root ganglion (DRG) neurons using the whole-cell patch-clamp technique. 2. In most of the DRG neurons examined (68/90, 75.5%) adenosine (1-10 microM) suppressed IGABA, while in some neurons examined, it potentiated (16/90, 17.8%) IGABA. It exerted no effects on IGABA in a few cells (6/90, 6.7%). 3. Adenosine shifted the GABA concentration-response curve downward with no significant change of the EC50. The maximal response to GABA was suppressed by 29.6 +/- 2.6%. The adenosine-induced inhibition of IGABA showed no voltage dependence. 4. 8-Cyclopentyl-1,3-dimethylxanthine (DPCPX; 1 microM), a selective A1 adenosine receptor antagonist, partially reversed adenosine inhibition of IGABA and completely blocked N6-cyclo-hexyladenosine (CHA; an A1 adenosine receptor agonist) inhibition of IGABA. DPCPX (1 microM) also blocked the suppression of IGABA by 2-chloroadenosine (CADO). CGS21680, a selective A2A adenosine receptor agonist, did not inhibit IGABA and DMPX, a selective A2A adenosine receptor antagonist, did not prevent adenosine inhibition of IGABA. 5. Intracellular application of H-7 (20 microM; a protein kinase C inhibitor) reversed adenosine inhibition of IGABA while inclusion of cAMP (1 mM), H-9 (20 microM; a protein kinase A inhibitor) and BAPTA (10 mM; a chelator of calcium ions) in the recording pipette did not affect the depression of IGABA by adenosine. IGABA was also suppressed by internal perfusion of PMA, a protein kinase C activator. 6. The results suggest that adenosine, as a neuromodulator, exerts a modulatory effect on the GABA-induced presynaptic inhibition in primary sensory transmission.
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PMID:Modulation by adenosine of GABA-activated current in rat dorsal root ganglion neurons. 917 95

Prolonged activation of an A2A adenosine receptor significantly inhibits the cellular response to subsequent stimulation (A2A desensitization). We have reported previously that activation of phosphodiesterase (PDE) contributes to A2A desensitization in PC12 cells. In the present study, we show that a type IV PDE (PDE4)-selective inhibitor (Ro 20-1724) effectively blocks the increase in PDE activity in desensitized cells. Thus, PDE4 appears to be the PDE specifically activated during A2A desensitization in PC12 cells. Prolonged treatment of PC12 cells with an A2A-selective agonist (CGS21680) leads to increased PDE4 activity in a dose-dependent manner, which can be blocked by an A2A-selective antagonist [8-(3-chlorostyryl)caffeine]. Using two PDE4 antibodies, we were able to demonstrate that the levels of two PDE4-immunoreactive bands (72 and 79 kDa) were increased significantly during A2A desensitization. Prolonged treatment with forskolin to elevate intracellular cyclic AMP contents also resulted in increased PDE4 activity. In addition, activation of PDE4 activity during A2A desensitization could be blocked by a protein kinase A (PKA)-selective inhibitor (H89) and was not observed in a PKA-deficient PC12 cell line (A123). Taken together, activation of PDE4 via a cyclic AMP/PKA-dependent pathway plays a critical role in dampening the signal of the A2A receptor.
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PMID:Activation of phosphodiesterase IV during desensitization of the A2A adenosine receptor-mediated cyclic AMP response in rat pheochromocytoma (PC12) cells. 928 56

The regulation of the furosemide-sensitive Na+-ATPase activity and ouabain-sensitive (Na+ + K+)ATPase activities from proximal tubules by adenosine was investigated. When the concentration of adenosine was increased the furosemide-sensitive ATPase activity decreased with maximal inhibition at 10(-8) M (56% of inhibition). However, the (Na+ + K+)ATPase activity was not affected by adenosine. Theophylline, an antagonist of P1 adenosine receptor, completely reversed the effect of adenosine on the furosemide-sensitive ATPase activity in a dose-response manner. The adenosine effect was mimicked by N6-cyclohexyladenosine (CHA), an agonist for A1 adenosine receptor. 5'-N-ethylcarboxamideadenosine (NECA), an agonist for A2 adenosine receptor, did not affect the furosemide-sensitive ATPase activity. When adenosine was used in the presence of 1 microg ml(-1) pertussis toxin, a Gi protein inhibitor, no change in the furosemide-sensitive ATPase activity was observed. The addition of 1 nM cholera toxin increased the Na+-ATPase activity by 60%. Adenosine decreased the cholera toxin stimulated Na+-ATPase in 42%, similar to the effect observed in the absence of cholera toxin. Dibutyryl-cAMP reversed the effect of adenosine in a dose dependent manner while the protein kinase A peptide inhibitor mimicked it. These data are compatible with a modulatory effect of adenosine on the Na+-ATPase activity via A1 subtype receptor.
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PMID:Effect of adenosine on the ouabain-insensitive Na+-ATPase activity from basolateral membrane of the proximal tubule. 937 25


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