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)

Galactosyltransferase (GALTase) activity was measured in differentiating PC12 cells induced by either forskolin or 2-chloroadenosine. The specific activity of GALTase in whole cells and isolated Golgi membranes increased as early as 3 h after initiating treatment with 2-chloroadenosine, and maximal activity was reached at approximately 12 h. In two mutant PC12 cell lines deficient in protein kinase A, both forskolin and 2-chloroadenosine failed to increase GALTase activity. The adenosine A2 receptor antagonist, xanthine amine congener, prevented 2-chloroadenosine stimulation of GALTase, demonstrating that this adenosine derivative was mediating its effect via the A2 receptor. These data suggest that GALTase activity during PC12 cell differentiation is regulated by cyclic AMP (cAMP)- and protein kinase A-dependent processes. In support of the role of cAMP in regulating GALTase activity were studies with murine PC carcinoma cells demonstrating that the greatest stimulation of GALTase activity occurred with cells treated with both retinoic acid and dibutyryl cAMP.
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PMID:Increase in beta-1,4-galactosyltransferase activity during PC12 cell differentiation induced by forskolin and 2-chloroadenosine. 164 58

Pretreatment of NG108-15 cells for 1 h with 1 microM phorbol 12-myristate,13-acetate produced no significant effect on the subsequent stimulation of adenylate cyclase activity by the IP receptor agonist, iloprost, the adenosine A2 receptor agonist, N-ethylcarboxamidoadenosine (NECA), or sodium fluoride, suggesting that protein kinase C activation does not produce desensitization in this system. Pretreatment of cells with 10 microM iloprost or forskolin for 17 h produced a decrease in the specific binding of [3H]iloprost, consistent with a decrease in IP receptor number. Iloprost pretreatment produced a decrease in responses to iloprost, NECA and sodium fluoride, whereas forskolin pretreatment produced a decrease in subsequent responsiveness to iloprost and NECA, but the response to sodium fluoride remained unaffected. The desensitization produced by forskolin could be completely inhibited by the inhibitor of protein kinase A and protein kinase C, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7), but H7 had no effect on the desensitization produced by iloprost.
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PMID:The role of protein kinase A and protein kinase C in prostanoid IP receptor desensitization in NG108-15 cells. 751 85

The adenosine A2a receptor inhibition of potassium (15 mM)-evoked GABA release from striatal nerve terminals has been examined. High extracellular calcium concentrations (4 mM) reduced the effect of the A2a receptor agonist CGS-21680 (1 nM). CGS-21680 inhibited GABA release in the presence of the L-type calcium channel blocker nifedipine, which itself inhibited evoked GABA release (by 16 +/- 4%). omega-Conotoxin inhibited the evoked release by 45 +/- 4% and prevented the action of CGS-21680. Forskolin and 8-bromo cyclic AMP both stimulated evoked GABA release at low concentrations, but at higher concentrations they abolished the inhibition by CGS-21680 without affecting the evoked release. The nonselective protein kinase inhibitor H-7 inhibited both the evoked release and the inhibition by CGS-21680, whereas the selective protein kinase A and G inhibitor HA-1004 had no effect on either evoked release or the action of CGS-21680. Pretreatment with pertussis toxin did not affect the A2a receptor-mediated inhibition. Therefore, the effect of A2a receptor stimulation was not mediated by protein kinases A or G but was inhibited by elevated cyclic AMP levels and mimicked by inhibitors of the N-type calcium channel and protein kinase C.
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PMID:Inhibition of striatal GABA release by the adenosine A2a receptor is not mediated by increases in cyclic AMP. 776 61

Chronic exposure to ethanol decreases receptor stimulation of cyclic AMP production. In PC 12 cells, chronic treatment with ethanol decreased the maximal stimulation of cyclic AMP accumulation by 2-chloroadenosine without altering the concentration of drug required for half-maximal stimulation. This desensitization was shown to occur after a 7-day exposure to 25 mM ethanol, which is comparable to the legal limit for intoxication in most states. When adenylate cyclase activity was measured directly in PC 12 cells permeabilized with Staphylococcal alpha-toxin, chronic ethanol treatment also decreased enzyme activity. After chronic ethanol exposure, cholera toxin-dependent [32P]ADP ribosylation of both the 44,000 and 52,000 dalton isoforms of the alpha-subunit of the stimulatory GTP-binding regulatory protein of adenylate cyclase (Gs alpha) was reduced. Similarly, an ethanol-induced decrease in the amounts of both isoforms of Gs alpha was found by immunoblot analysis. This decrease in Gs alpha levels was not observed after chronic ethanol exposure of A126-1B2-1 cells, which are functionally deficient in protein kinase A. Immunoblot analysis using an antiserum that recognizes both the alpha-subunit of the inhibitory GTP-binding regulatory protein of adenylate cyclase (Gi alpha)1 and Gi alpha 2 indicated that chronic ethanol treatment did not alter membrane levels of these GTP-binding proteins. Chronic ethanol exposure of PC 12 cells did not alter the affinity of the adenosine A2 receptor for the radioligand [3H]CGS 21680, nor was there a change in the density of binding sites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Ethanol-induced desensitization of adenylate cyclase: role of the adenosine receptor and GTP-binding proteins. 838 87

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

Many Gs-linked receptors have been reported to use multiple signalling pathways in transfected cels but few in their normal cell environment. We show that the adenosine A2a receptor uses two signalling pathways to increase the release of acetylcholine from striatal nerve terminals. One pathway involves activation of Gs, adenylyl acylase, protein kinase A, and P-type calcium channels; the other is mediated by a cholera toxin-insensitive G protein, protein kinase C, and N-type calcium channels. The effects of these two pathways are not additive, the second pathway being inhibited by the first; but they are equally sensitive to the A2a receptor antagonist KF17837. This demonstrates that the A2a receptor activates two signalling systems in striatal cholinergic neurons.
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PMID:Dual signalling by the adenosine A2a receptor involves activation of both N- and P-type calcium channels by different G proteins and protein kinases in the same striatal nerve terminals. 866 16

Monocytes and macrophages produce tumor necrosis factor-alpha (TNF alpha) in response to microbial products including endotoxin. TNF alpha is a potent primer of neutrophil (PMN) oxidative activity. Certain xanthine phosphodiesterase (PDE) inhibitors such as pentoxifylline have been shown to inhibit stimulated oxidative activity in PMN. In the present study, the non-xanthine PDE type IV inhibitor rolipram (4-[3'-cyclopentyloxy-4'-methoxyphenyl]-2-pyrrolidone) alone and in combination with adenosine is examined as a potential modulator of TNF alpha-primed PMN oxidative activity. Attainable in vivo concentrations of rolipram and physiological concentrations of adenosine alone and together synergistically decreased rhTNF alpha-primed suspended PMN oxidative activity stimulated by the chemoattractant f-met-leu-phe. The rolipram effect was reversible by washing, and rolipram had a comparable effect if added before or after priming, indicating that its effect was on the primed response rather than on priming per se. In addition, rolipram especially when combined with adenosine, decreased rhTNF alpha-stimulated PMN adherence to a fibrinogen-coated surface, and the oxidative burst of rhTNF alpha-stimulated adherent PMN. The specific adenosine A2a receptor agonists CGS 21680 and WRC-0474 had comparable activity to adenosine in these experiments. Adenosine (or CGS 21680) combined with rolipram synergistically increased f-met-leu-phe-stimulated PMN cAMP content. The effects of both adenosine and rolipram with adenosine could be only partly counteracted by treatment of the PMN with the protein kinase A inhibitor KT 5720, indicating that protein phosphorylation is only partially involved. Rolipram activity was about 1000 x (by molar concentration) greater than pentoxifylline in comparable assays. Thus, rolipram, especially when combined with adenosine, has potent modulating effects on PMN activation and may be useful in decreasing inflammatory tissue damage in patients with sepsis.
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PMID:The specific type IV phosphodiesterase inhibitor rolipram combined with adenosine reduces tumor necrosis factor-alpha-primed neutrophil oxidative activity. 870 44

1. The cell-attached and cell-free configurations of the patch-clamp technique were used to investigate whether external ATP and its derivatives modulate channel activity in outer hair cells freshly isolated from the guinea-pig cochlea. 2. Submicromolar concentrations of ATP stimulated a non-selective cation channel with a conductance of about 25 pS. The ATP-elicited stimulation was partly blocked by the membrane-permeant blocker 3',5-dichlorodiphenylamine-2-carboxylic acid (DCDPC), and mimicked by the calcium ionophore, ionomycin, suggesting that the channel activated by ATP is identical to a previously reported calcium-activated non-selective (CAN) cation channel. 3. The P2x agonist beta, gamma-methylene-ATP (beta, gamma-MeATP, 10 microM) and the P2Y agonist 2-methyl-thio-ATP (2-MeSATP, 1 microM) both activated CAN channels. The effect of ATP was inhibited by the P2 antagonist suramin but not by the P2Y antagonist Reactive Blue 2. These results suggest that both purinergic receptors are involved in the ATP-evoked response and that internal calcium acts as a second messenger for opening CAN channels. 4. In contrast, adenosine inhibited CAN channels. This effect was reproduced by the A2 agonist 5'-N-ethylcarboxyamidoadenosine (NECA) and the permeant cAMP analogue 8-bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP), but not by the A1 agonist N6-cyclo-hexyladenosine (CHA). CAN channels were also inhibited when the catalytic subunit of protein kinase A was applied internally on inside-out patches, suggesting that adenosine A2 receptor downregulates CAN channels via a cAMP-dependent phosphorylation.
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PMID:Modulation by purines of calcium-activated non-selective cation channels in the outer hair cells of the guinea-pig cochlea. 881 8

Using receptor-selective agonists and antagonists, the possible presence of both A2a and A2b adenosine receptor subtypes coupled to activation of adenylyl cyclase was investigated in NG108-15 neuroblastoma x glioma hybrid cells. The relatively non-selective adenosine receptor agonist 5'-(N-ethyl carboxamido)-adenosine (NECA; 1 nM-300 microM) produced a biphasic increase in adenylyl cyclase activity in cell homogenates, best fitted to two components with high (EC50 0.7 microM) and low (EC50 16.0 microM) potency, respectively. The selective adenosine A2a receptor agonist CGS-21680 (1 nM-300 microM) also produced a biphasic increase in adenylyl cyclase. The NECA-dependent increase in adenylyl cyclase activity was almost completely inhibited by the non-selective adenosine receptor antagonist xanthine amine congener (XAC; 30 microM), but only partially inhibited by the selective A2a adenosine antagonist 8-(3-chlorostyryl)caffeine (CSC; 1 microM). Experiments were also performed to investigate the time course of NECA-induced desensitization of putative A2a and A2b receptor responses. The A2a-response was quantified using 10 microM CGS-21680, whilst the A2b response was quantified using 100 microM NECA in the presence of 1 microM CSC. The t0.5 for desensitization for each subtype was found to be around 20 min. Neither activation (with dibutyryl cAMP; 1 mM) nor inhibition (with H-89; 10 microM) of cyclic AMP-dependent protein kinase altered the ability of NECA pretreatment to desensitize A2a or A2b receptor-activated adenylyl cyclase. However zinc (200 microM), an inhibitor of G-protein coupled receptor kinase 2 (GRK2), significantly reversed the agonist-induced desensitization of A2a and A2b receptor-activated adenylyl cyclase. These experiments suggest the co-existence of A2a and A2b receptors coupled in a stimulatory fashion to adenylyl cyclase in NG108-15 cells. Furthermore desensitization of A2a and A2b responses occurs at the same rate and may involve a G-protein-coupled receptor kinase.
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PMID:Evidence for co-expression and desensitization of A2a and A2b adenosine receptors in NG108-15 cells. 951 70

The mechanisms by which adenosine regulates the inflammatory reaction are poorly characterized. In this study, we investigated the effects of adenosine on neutrophil actin polymerization elicited by the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) or IgG-opsonized yeast particles. We used bodipy-phallacidin staining in combination with flow cytometry and found that adenosine markedly reduced actin polymerization triggered by IgG-yeast, whereas the effect on the fMLP-response was less pronounced. Similar or even more pronounced effects were obtained with the adenosine A2 receptor agonist 5'-N-ethylcarboxamidoadenosine (NECA), suggesting an A2 receptor-mediated mechanism. The following observations indicate that the A2 receptor-induced effects involve the cAMP-protein kinase A (PKA) signaling pathway: (1) a combination of NECA and the cAMP-specific phosphodiesterase (PDE) inhibitor Ro 20-1724 raised the cAMP content in both unstimulated and stimulated neutrophils and also further inhibited the actin dynamics; (2) the PKA inhibitor H89 reversed the inhibitory effects of NECA on the actin dynamics; (3) Ro 20-1724, isoproterenol and dibutyryl cAMP (DBcAMP) reduced actin polymerization in almost the same way as NECA did. NECA together with Ro 20-1724 impaired the fMLP-induced shape changes and cortical accumulation of actin filaments. In contrast, H89 potentiated the fMLP-induced formation of a submembranous ring of actin filaments. Neutrophils phagocytosing yeast particles in the presence of NECA and Ro 20-1724 were predominantly round in shape, and their ability to extend actin-rich pseudopods around the prey was reduced. These effects were partly antagonized by H89. In correlation with the effects on actin polymerization, NECA more effectively diminished IgG-induced upregulation of the beta2 integrin CD11b/CD18 than such upregulation induced by fMLP. The inhibitory effects of A2-receptor activation on actin dynamics and beta2 integrin expression in neutrophils exposed to IgG-yeast were also associated with a cAMP-dependent reduction of the phagocytic capacity. In conclusion, we show that adenosine inhibits actin dynamics and shape changes in neutrophils via a cAMP-dependent pathway. This finding further characterizes the mechanisms by which adenosine functions as an important modulator of the inflammatory response.
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PMID:Adenosine inhibits actin dynamics in human neutrophils: evidence for the involvement of cAMP. 954 70


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