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)

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

1. Glutamate and other amino acids are the main excitatory neurotransmitters in many brain regions, including the hippocampus, by activating ion channel-coupled glutamate receptors, as well as metabotropic receptors linked to G proteins and second messenger systems. Several conditions which promote the release of glutamate, like frequency stimulation and hypoxia, also lead to an increase in the extracellular levels of the important neuromodulator, adenosine. We studied whether the activation of different subgroups of metabotropic glutamate receptors (mGluR) could modify the known inhibitory effects of a selective adenosine A1 receptor agonist on synaptic transmission in the hippocampus. The experiments were performed on hippocampal slices taken from young (12-14 days old) rats. Stimulation was delivered to the Schaffer collateral/commissural fibres, and evoked field excitatory postsynaptic potentials (fe. p.s.p.) recorded extracellularly from the stratum radiatum in the CAI area. 2. The concentration-response curve for the inhibitory effects of the selective adenosine A1 receptor agonist, N6-cyclopentyladenosine (CPA; 2-50 nM), on the fe.p.s.p. slope (EC50 = 12.5 (9.2-17.3; 95% confidence intervals)) was displaced to the right by the group I mGluR selective agonist, (R,S)-3,5-dihydroxyphenylglycine (DPHG; 10 microM) (EC50 = 27.2 (21.4-34.5) nM, n = 4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by DHPG (10 microM) was blocked in the presence of the mGluR antagonist (which blocks group I and II mGluR), (R,S)-alpha-methyl-4-carboxyphenylglycine (MCPG; 500 microM). DHPG (10 microM) itself had an inhibitory effect of 20.1 +/- 1.9% (n = 4) on the fe.p.s.p. slope. 3. The concentration-response curves for the inhibitory effects of CPA (2-20 nM) on the fe.p.s.p. slope were not modified either in the presence of the group II mGluR selective agonist, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine (L-CCG-I; 1 microM), or in the presence of the non-selective mGluR agonist (which activates both group I and II mGluR), (IS,3R)-1-aminocyclopentyl-1,3-dicarboxylate (ACPD; 100 microM). L-CCG-I had no consistent effects and ACPD (100 microM) decreased by 19.4 +/- 1.8% (n = 4) the fe.p.s.p. slope. 4. The concentration-response curve for the inhibitory effects of CPA (2-100 nM) on the fe.p.s.p. slope (EC50 = 8.2 (6.9-9.6) nM) was displaced to the right by the group III mGluR selective agonist, L-2-amino-4-phosphonobutyrate (L-AP4; 25 microM) (EC50 = 17.7 (13.1-21.9) nM, n = 4). The attenuation of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope by L-AP4 (25 microM) was blocked in the presence of the mGluR antagonist (selective for the group III mGluR), (R,S)-alpha-methyl-4-phosphonophenylglycine (MPPG; 200 microM). 5. Both the direct effect of DHPG on synaptic transmission and the attenuation of the inhibitory effect of CPA (10 nM) were prevented in the presence of the protein kinase C selective inhibitors, staurosporine (1 microM) or chelerythrine (5 microM), and thus attributed to activation of protein kinase C. 6. The attenuation by L-AP4 (25 microM) of the inhibitory effect of CPA (10 nM) on the fe.p.s.p. slope was also prevented by the protein kinase C selective inhibitors, staurosporine (1 microM) or chelerythrine (5 microM), and thus attributed to activation of protein kinase C. But this effect seemed to be distinct from the direct effect of L-AP4 (25 microM) on synaptic transmission, which was not modified by the protein kinase C selective inhibitors. 7. We conclude that agonists of metabotropic glutamate receptors (Groups I and III) are able to attenuate the inhibitory effects of adenosine A1 receptor activation in the hippocampus. This interaction may have pathophysiological relevance in hypoxia, in which there is marked release of both excitatory amino acids and the important endogenous neuroprotective substance, adenosine.
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PMID:Influence of metabotropic glutamate receptor agonists on the inhibitory effects of adenosine A1 receptor activation in the rat hippocampus. 928 86

Neuropeptide Y (NPY) significantly potentiates the constrictor actions of noradrenaline and ATP on blood vessels via a pertussis toxin (PTX)-sensitive mechanism involving Gi/o (alpha beta gamma) protein subunits (Gi/o, GTP-binding proteins sensitive to PTX). In Chinese hamster ovary K1 (CHO K1) cells expressing specific receptors for these neurotransmitters, stimulation of Gi/o protein-coupled receptors for NPY and other neurotransmitters can augment the Gq/11-coupled (Gq/11, GTP-binding proteins insensitive to PTX) alpha 1B adrenoceptor- or ATP receptor-induced arachidonic acid (AA) release and inositol phosphate (IP) production (early events which may precede vasoconstriction). In this study, we have assessed the role of G beta gamma subunits in the synergistic interaction between Gi/o- (NPY Y1, 5-hydroxytryptamine 5-HT1B, adenosine A1) and Gq/11- [ATP P2Y2 (P2U)]-coupled receptors on AA release by using the specific abilities of regions of the beta-adrenergic receptor kinase (beta ARK1 residues 495-689) and the transducin alpha subunit to associate with G-protein beta gamma subunit dimers and to act as G beta gamma subunit scavengers. Transient expression of beta ARK1(495-689) in CHO K1 cells heterologously expressing NPY Y1 receptors had no significant effect on the PTX-insensitive ability of ATP to stimulate AA release. Stimulation of NPY Y1 receptors (as well as the endogenous 5-hydroxytryptamine 5-HT1B receptor and the transiently expressed human adenosine A1 receptor) resulted in a PTX-sensitive augmentation of ATP-stimulated AA release, which was inhibited by expression of both G beta gamma subunit scavengers. Expression of beta ARK1(495-689) similarly inhibited NPY Y1 receptor augmentation of ATP-stimulated IP production (a measure of phospholipase C activity), a step thought to precede the NPY Y1 receptor-augmented protein kinase C-dependent AA release previously observed in these cells. These experiments demonstrate that G beta gamma subunits, as inhibited by two different G beta gamma scavengers, significantly contribute to the synergistic interaction between NPY Y1 Gi/o- and Gq/11-coupled receptor activity, and are required for the augmentation of IP production and AA release observed in this model cell system.
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PMID:Role of G-protein beta gamma subunits in the augmentation of P2Y2 (P2U)receptor-stimulated responses by neuropeptide Y Y1 Gi/o-coupled receptors. 935 46

We have studied which type/s of Ca2+-channel/s support glutamate exocytosis and its modulation by presynaptic receptors in cerebrocortical nerve terminals. Depolarization of nerve terminals with 30 mM KCl induced a Ca2+-dependent release of 3.64 +/- 0.25 nmol/mg of protein. The addition of either 2 microM omega-conotoxin-GVIA or 200 nM omega-agatoxin-IVA reduced the KCl-evoked release by 47.7 +/- 3.5% and 70.4 +/- 8.9% respectively, and by 85.7 +/- 4.1% when both toxins were co-applied. The activation of adenosine A1 receptors with N6-cyclohexyladenosine or the activation of metabotropic glutamate receptors with L(+)-2-amino-4-phosphonobutyrate inhibited the KCl-evoked release by 41.0 +/- 5.9 and 54.3 +/- 10% respectively. The extent of these inhibitions was not altered by the prior addition of 2 microM omega-conotoxin-GVIA but they were significantly enhanced when omega-agatoxin-IVA was added together with the adenosine A1 receptor agonist or the metabotropic glutamate receptor agonist, suggesting that omega-conotoxin-GVIA-sensitive and not omega-agatoxin-IVA-sensitive Ca2+-channels are involved in the action of these inhibitory receptors. By contrast, the facilitation of glutamate release that follows the activation of the protein kinase C, either with phorbol esters or with the stimulation of phospholipase C-linked metabotropic receptors, was expressed by both omega-conotoxin-GVIA-sensitive and omega-agatoxin-sensitive Ca2+-channels. It is concluded that different Ca2+-channels support the modulation of glutamate release by presynaptic receptors.
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PMID:Presynaptic modulation of glutamate release targets different calcium channels in rat cerebrocortical nerve terminals. 942 Nov 62

1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro- and macrovascular complications of diabetes. 3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance. 4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.
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PMID:Mechanisms of insulin resistance and new pharmacological approaches to metabolism and diabetic complications. 949 93

The KCl-evoked exocytotic release of glutamate from rat cerebrocortical synaptosomes is inhibited by a presynaptic adenosine A1 receptor decreasing voltage-activated Ca2+ entry. This inhibition was transiently suppressed by (1S,3R)-1-aminocyclopenthyl-1,3-dicarboxylate (ACPD) but was restored within 1 min in the continued presence of the metabotropic agonist. In the presence of 2 microM arachidonic acid ACPD initiated a prolonged suppression of the adenosine-mediated inhibition persisting for at least 10 min. Arachidonic acid (20-40 pmol) was bound per mg synaptosomal protein. Prolonged ACPD-mediated phosphorylation of the protein kinase C (PKC) substrate myristoylated alanine-rich C-kinase substrate (MARCKS) was detected in the presence but not the absence of arachidonic acid, but arachidonic acid added 2 min after ACPD was ineffective. It is concluded that arachidonic acid synergistically prolongs the metabotropic glutamate receptor-mediated activation of presynaptic PKC, suppressing inhibitory receptor pathways.
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PMID:Arachidonic acid potentiates the duration of the metabotropic, protein kinase C-mediated, suppression of the inhibitory adenosine A1 receptor pathway in glutamatergic nerve terminals from rat cerebral cortex. 959 7

It has been suggested that adenosine cardioprotection occurs via adenosine A1 receptor-mediated activation of protein kinase C (PKC). However, adenosine has well-known vasodilatory effects in the myocardium, whereas PKC is a vasoconstrictor. This study examined whether adenosine A1 receptor activation alters the effects of the PKC activator. 1,2-dioctanoyl-s,n-glycerol (DOG) in isolated perfused rat hearts (left-ventricular developed pressure) and rat ventricular myocytes ([Ca2+]i and cell shortening). Exposure to DOG decreased left-ventricular developed pressure by 30%, an effect that was completely reversible. Pretreatment of isolated hearts with either the PKC inhibitor chelerythrine or the adenosine A1 agonist 2-chloro-N6-cyclo-cyclo-isolated pentlyadenosine (CCPA) attenuated the negative inotropic effects of DOG. In the isolated myocytes, DOG decreased [Ca2+]i and cell shortening by 25 and 28%, respectively, effects that were attenuated by both chelerythrine and CCPA. The CCPA attenuation of the DOG-induced decrease in [Ca2+]i and cell shortening was blocked by pretreating the myocytes with the adenosine A1 antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). These results indicate that in rat ventricular myocardium, adenosine A1 receptor activation attenuates the apparent PKC-dependent negative inotropic effects of DOG via preservation of [Ca2+]i levels.
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PMID:Adenosine A1 receptor stimulation antagonizes the negative inotropic effects of the PKC activator dioctanoylglycerol. 961 32

Although the G protein betagamma dimer is an important mediator in cell signaling, the mechanisms regulating its activity have not been widely investigated. The gamma12 subunit is a known substrate for protein kinase C, suggesting phosphorylation as a potential regulatory mechanism. Therefore, recombinant beta1 gamma12 dimers were overexpressed using the baculovirus/Sf9 insect cell system, purified, and phosphorylated stoichiometrically with protein kinase C alpha. Their ability to support coupling of the Gi1 alpha subunit to the A1 adenosine receptor and to activate type II adenylyl cyclase or phospholipase C-beta was examined. Phosphorylation of the beta1 gamma12 dimer increased its potency in the receptor coupling assay from 6.4 to 1 nM, changed the Kact for stimulation of type II adenylyl cyclase from 14 to 37 nM, and decreased its maximal efficacy by 50%. In contrast, phosphorylation of the dimer had no effect on its ability to activate phospholipase C-beta. The native beta1gamma10 dimer, which has 4 similar amino acids in the phosphorylation site at the N terminus, was not phosphorylated by protein kinase C alpha. Creation of a phosphorylation site in the N terminus of the protein (Gly4 --> Lys) resulted in a beta1 gamma10G4K dimer which could be phosphorylated. The activities of this beta gamma dimer were similar to those of the phosphorylated beta1 gamma12 dimer. Thus, phosphorylation of the beta1 gamma12 dimer on the gamma subunit with protein kinase C alpha regulates its activity in an effector-specific fashion. Because the gamma12 subunit is widely expressed, phosphorylation may be an important mechanism for integration of the multiple signals generated by receptor activation.
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PMID:Phosphorylation of the G protein gamma12 subunit regulates effector specificity. 970 36

1. The mitogen-activated protein (MAP) kinase signalling pathway can be activated by a variety of heterotrimeric Gi/Go protein-coupled and Gq/G11 protein-coupled receptors. The aims of the current study were: (i) to investigate whether the Gi/Go protein-coupled adenosine A1 receptor activates the MAP kinase pathway in transfected Chinese hamster ovary cells (CHO-A1) and (ii) to determine whether adenosine A1 receptor activation would modulate the MAP kinase response elicited by the endogenous P2Y2 purinoceptor. 2. The selective adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) stimulated time and concentration-dependent increases in MAP kinase activity in CHO-A1 cells (EC50 7.1+/-0.4 nM). CPA-mediated increases in MAP kinase activity were blocked by PD 98059 (50 microM; 89+/-4% inhibition), an inhibitor of MAP kinase kinase 1 (MEKI) activation, and by pre-treating cells with pertussis toxin (to block Gi/Go-dependent pathways). 3. Adenosine A1 receptor-mediated activation of MAP kinase was abolished by pre-treatment with the protein tyrosine inhibitor, genistein (100 microM; 6+/-10% of control). In contrast, daidzein (100 microM), the inactive analogue of genistein had no significant effect (96+/-12 of control). MAP kinase responses to CPA (1 microM) were also sensitive to the phosphatidylinositol 3-kinase inhibitors wortmannin (100 nM; 55+/-8% inhibition) and LY 294002 (30 microM; 40+/-5% inhibition) but not to the protein kinase C (PKC) inhibitor Ro 31-8220 (10 microM). 4. Activation of the endogenous P2Y2 purinoceptor with UTP also stimulated time and concentration-dependent increases in MAP kinase activity in CHO-A1 cells (EC50=1.6+/-0.3 microM). The MAP kinase response to UTP was partially blocked by pertussis toxin (67+/-3% inhibition) and by the PKC inhibitor Ro 31-8220 (10 microm; 45+/-5% inhibition), indicating the possible involvement of both Gi/Go protein and Gq protein-dependent pathways in the overall response to UTP. 5. CPA and UTP stimulated concentration-dependent increases in the phosphorylation state of the 42 kDa and 44 kDa forms of MAP kinase as demonstrated by Western blotting. 6. Co-activation of CHO-A1 cells with CPA (10 nM) and UTP (1 microM) produced synergistic increases in MAP kinase activity which were not blocked by the PKC inhibitor Ro 31-8220 (10 microM). 7. Adenosine A1 and P2Y2 purinoceptor activation increased the expression of luciferase in CHO cells transfected with a luciferase reporter gene containing the c-fos promoter. However, co-activating these two receptors produced only additive increases in luciferase expression. 8. In conclusion, our studies have shown that the transfected adenosine A1 receptor and the endogenous P2Y2 purinoceptor couple to the MAP kinase signalling pathway in CHO-A1 cells. Furthermore, co-stimulation of the adenosine A1 receptor and the P2Y2 purinoceptor produced synergistic increases in MAP kinase activity but not c-fos mediated luciferase expression.
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PMID:Human adenosine A1 receptor and P2Y2-purinoceptor-mediated activation of the mitogen-activated protein kinase cascade in transfected CHO cells. 972 63

Exogenously administered adenosine agonist will protect myocardium against infarction during ischemia. However, long-term exposure to adenosine agonists is associated with loss of this protection. To determine why this protection is lost, isolated, perfused rabbit hearts were studied after administration of R(-)-N6-(2-phenylisopropyl)adenosine (PIA), 0.25 mg/h IP, for 3-4 days to intact animals. All hearts experienced 30 min of regional ischemia and 120 min of reperfusion. Control groups 1 and 2 were untreated. In group 1 this ischemia/reperfusion was the only intervention, whereas group 2 hearts were preconditioned with a cycle of 5 min global ischemia/10 min reperfusion preceding the 30 min regional ischemia. Groups 3-5 had been chronically exposed to PIA. Group 3 hearts had 1 preconditioning ischemia/reperfusion cycle before the prolonged ischemia. Group 4 received a 5 min infusion of 0.1 micromol/L phenylephrine in lieu of global ischemia, whereas group 5 was instead treated with 1 micromol/L carbachol. Infarct size averaged 32% of the risk zone in group 1, whereas ischemic preconditioning limited infarction to 8.2% in group 2. Prolonged exposure of group 3 hearts to PIA resulted in the inability of preconditioning with 5 min global ischemia to protect (28.7+/-4.4% infarction). However, protection was restored by either phenylephrine, an agonist of alpha1-adrenergic receptors which couple to Gq and stimulate PKC, or carbachol, an agonist of M2-muscarinic receptors which couple instead to Gi as do adenosine A1 receptors (5.2+/-1.7% and 9.2+/-2.1% infarction, resp.). Therefore, cross tolerance to ischemic preconditioning develops after chronic PIA infusion. Since both the Gi and the PKC components of the preconditioning pathway were shown to be intact, tolerance must have been related to downregulation or desensitization of the A1 adenosine receptor.
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PMID:Loss of myocardial protection from ischemic preconditioning following chronic exposure to R(-)-N6-(2-phenylisopropyl)adenosine is related to defect at the adenosine A1 receptor. 977 81


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