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)

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. The A type of acetylcholine response of Helix neurons is downmodulated by low concentrations of GABA that do not elicit any measurable change in membrane potential or conductance. 2. We find that these physiological actions are associated with an increase in both intracellular cyclic AMP levels and 45Ca2+ influx. 3. The modulation of the acetylcholine response by GABA is blocked when the neurons are injected with EGTA to prevent a rise in intracellular Ca2+ concentration or when tolbutamide, an inhibitor of protein kinase A, is applied. 4. These results are consistent with the effects of GABA being mediated by a metabotropic GABA receptor that is activated at very low GABA concentrations and mediates modulation of the acetylcholine response via regulation of intracellular Ca2+ and cyclic AMP levels.
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PMID:Metabotropic GABA receptors regulate acetylcholine responses on snail neurons. 919 95

We have previously reported dual effects of mu-opioids on N-methyl-D-aspartate (NMDA)-receptor-mediated synaptic events in the hippocampal dentate gyrus: an indirect facilitating effect via suppression of GABAergic interneurons (disinhibition) and a direct inhibitory effect in the presence of gamma-aminobutyric acid-A (GABA(A)) antagonists. The cellular mechanism underlying the inhibitory effect of mu-opioids remains to be determined. In the present study we examine the role of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase (PKA) in mu-opioid-induced inhibition of NMDA currents in rat hippocampal slices. NMDA-receptor-mediated excitatory postsynaptic currents (NMDA EPSCs) were evoked by stimulating the lateral perforant path and were recorded from dentate granule cells with the use of whole cell voltage-clamp techniques in the presence of the GABA(A) antagonist and a non-NMDA type of glutamate receptor antagonist. Two selective mu-agonists, [N-MePhe3, D-Pro4]-morphiceptin and [D-Ala2, N-MePhe4, Gly-ol5]-enkephalin, induced dose-dependent inhibition of NMDA EPSCs in a concentration range of 0.3-10 microM. This inhibitory effect could be completely reversed by the opioid antagonists naloxone or prevented by a selective mu-antagonist cyprodime, but was not affected by removal of Mg2+ from the external perfusion medium. Intracellular application of pertussis toxin (PTX) into the granule cell via whole cell recording pipettes completely prevented mu-opioid-induced reduction in NMDA currents, suggesting that a postsynaptic mechanism involving PTX-sensitive G proteins might be responsible for the inhibitory action of mu-opioids. Further studies were conducted to identify the intracellular messengers that coupled with G proteins and transduced the effect of mu-opioids in granule cells. The adenylate cyclase activator forskolin was found to enhance NMDA-receptor-mediated synaptic responses and to reverse the inhibitory effect of mu-opioids. Sp-cAMPS, a specific PKA activator, also enhanced NMDA EPSCs, whereas the PKA inhibitor Rp-cAMPS reduced NMDA EPSCs and occluded further inhibition of the current by mu-opioids. These findings strongly suggest that NMDA receptor function is subject to the modulation by PKA, and that mu-opioids can inhibit NMDA currents through suppression of the cAMP cascade in the postsynaptic neuron. Combined with our previous findings, the present results also indicate that mu-opioids can modulate NMDA-receptor-mediated synaptic activity in a complex manner. The net effect of mu-opioids in the dentate gyrus may depend on the interplay between its disinhibitory action, which facilitates NMDA-receptor-mediated responses, and its inhibitory action on the cAMP cascade.
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PMID:Involvement of cAMP-dependent protein kinase in mu-opioid modulation of NMDA-mediated synaptic currents. 930 10

Sucrose gap recordings from the dorsal roots of isolated, hemisected frog spinal cords were used to determine the effects of metabotropic L-glutamate receptor activation on primary afferent terminals by (+/-)-1-amino-trans-1,3-cyclopentane-dicarboxylic acid (t-ACPD). Dorsal root potentials evoked by ventral root volleys were significantly reduced by t-ACPD (30 microM), as were GABA- and muscimol-induced afferent terminal depolarizations. The effects of t-ACPD on GABA-depolarizations depended upon activation of group I metabotropic glutamate receptors, i.e. the effects were blocked by the group I/II antagonist (RS)-alpha-methyl-4-carboxyphenylglycine, but not by the group II antagonist alpha-methyl-(2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine or the group III antagonist alpha-methyl-(S)-2-amino-4-phosphonobutyrate and were mimicked by the group I agonist 3,5-dihydroxyphenylglycine but were not mimicked by the group III agonist (S)-2-amino-4-phosphonobutyrate. Increasing the intracellular concentration of 3'-5'-cyclic adenosine monophosphate with 8-bromo-cAMP, forskolin, and 3-isobutyl-1-methylxanthine significantly reduced GABA depolarizations, but the protein kinase inhibitors Rp-adenosine 3,5-cyclic monophosphothioate triethylamine and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide did not alter t-ACPD's depression of GABA depolarizations. The actions of t-ACPD on GABA depolarizations were neither mimicked nor blocked by phorbol-12-myristate 13-acetate, thapsigargin, staurosporine, or arachidonic acid, presumptive indications that the effects of t-ACPD did not involve phosphoinositide hydrolysis, the release of Ca2+ from intracellular stores, or the formation of arachidonate. t-ACPD's effects on GABA depolarizations were blocked by 20 mM Mg2+, the broad spectrum L-glutamate antagonist kynurenate, and the selective N-methyl-D-aspartate antagonist D(-)-2-amino-5-phosphonovaleric acid, but not by the non-N-methyl-D-aspartate antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. Low concentrations of N-methyl-D-aspartate (10 microM) mimicked the effect of t-ACPD on GABA responses. These results suggest that t-ACPD's depression of GABA depolarizations involves an indirect, three-stage mechanism that includes activation of Group I metabotropic glutamate receptors on interneurons and/or on afferent terminals, the release of L-glutamate from the latter structures, and the activation of N-methyl-D-aspartate receptors on primary afferent terminals. The depression of GABA depolarizations caused by the release of L-glutamate from afferent terminal and/or interneurons leads to a block of presynaptic inhibition (produced in the frog spinal cord by GABA) resulting in a positive feed-forward amplification of reflex transmission.
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PMID:Role of metabotropic glutamate receptors in the depression of GABA-mediated depolarization of frog primary afferent terminals. 933 Mar 69

Using patch-clamp techniques we studied several aspects of intracellular GABA(A) and glycine Cl- current regulation in cortical and spinal cord neurons, respectively. Activation of PKA with a permeable analog of cyclic AMP (cAMP) produced a potentiation of the Cl- current activated with glycine, but not of the current induced with GABA. The inactive analog was without effect. Activation of PKC with 1 microM PMA reduced the amplitude of the GABA(A) and glycine currents. Internal application of 1 mM cGMP, on the other hand, had no effect on the amplitude of either current. The amplitude of these inhibitory currents changed slightly during 20 min of patch-clamp recording. Internal perfusion of the neurons with 1 microM okadaic acid, a phosphatase inhibitor, induced potentiation in both currents. The amplitude of GABA(A) and glycine currents recorded with 1 mM internal CaCl2 and 10 mM EGTA (10 nM free Ca2+) decayed by less than 30% of control. Increasing the CaCl2 concentration to 10 mM (34 microM free Ca2+) induced a transient potentiation of the GABA(A) current. A strong depression of current amplitude was found with longer times of dialysis. The glycine current, on the contrary, was unchanged by increasing the intracellular Ca2+ concentration. Activation of G proteins with internal FAl4- induced an inhibition of the GABA(A) current, but potentiated the amplitude of the strychnine-sensitive Cl- current. These results indicate that GABA(A) and glycine receptors are differentially regulated by activation of protein kinases, G proteins and Ca2+. This conclusion supports the existence of selectivity in the intracellular regulation of these two receptor types.
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PMID:Differential intracellular regulation of cortical GABA(A) and spinal glycine receptors in cultured neurons. 937 87

Cholinergic interneurons have been implicated in striatally mediated associative learning. In classical conditioning paradigms, conditioned stimuli trigger a transient suppression of neuronal activity that is dependent upon an intact dopaminergic innervation. Our hypothesis was that this suppression reflected dopaminergic enhancement of sensory-linked GABAergic input. As a test, the impact of dopamine on interneuronal GABA(A) receptor function was studied by combined patch-clamp recording and single-cell reverse transcription PCR. Activation of D5 dopamine receptors reversibly enhanced a Zn2+-sensitive component of GABA(A) currents. Although dependent upon protein kinase A (PKA) activation, the modulation was blocked by protein phosphatase 1 (PP1) inhibition, suggesting it was dependent upon dephosphorylation. These results establish a novel mechanism by which intrastriatally released dopamine mediates changes in GABAergic signaling that could underlie the initial stages of associative learning.
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PMID:D5 dopamine receptors enhance Zn2+-sensitive GABA(A) currents in striatal cholinergic interneurons through a PKA/PP1 cascade. 939 May 24

All mammalian GABA(A) receptor beta subunits contain a conserved consensus site for phosphorylation by a number of serine/threonine protein kinases. This site corresponds to Serine 410 of the beta2 subunit and Serine 409 of the beta3 subunit, each of which lies within the conserved sequence R-R-R-X-S-L-Q-K, where X = A (beta1, beta2 and beta4) or S (beta3). We have analysed the phosphorylation of the beta2 and beta3 subunits of the murine GABA(A) receptor by expressing the large intracellular domains of these subunits as soluble fusion proteins in E. coli. The intracellular domain of the beta2 subunit was phosphorylated to high stoichiometry by both cAMP- and cGMP-dependent protein kinases, protein kinase C and Ca2+/calmodulin type II-dependent protein kinase in vitro. Site-directed mutagenesis identified Serine 410 as the single site within the beta2 subunit phosphorylated by these four protein kinases. Using similar methodologies, Serine 409 of the beta3 subunit was shown to be a substrate for phosphorylation by these protein kinases. Serine 408 was also seen to be phosphorylated by protein kinase C and Serine 383 was phosphorylated by Ca2+/calmodulin type II-dependent protein kinase. Since beta subunits are believed to be essential for robust GABA(A) receptor expression, these results suggest a critical role for conserved phosphorylated amino acids within the beta subunits in coordinating cellular regulation of GABA(A) receptors via multiple protein kinases.
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PMID:Conserved phosphorylation of the intracellular domains of GABA(A) receptor beta2 and beta3 subunits by cAMP-dependent protein kinase, cGMP-dependent protein kinase protein kinase C and Ca2+/calmodulin type II-dependent protein kinase. 942 25

The effect of calcium-phospholipid-dependent protein kinase (PKC) activation on neurosteroid modulation of the GABA(A) receptor was examined in Xenopus oocytes expressing human recombinant alpha1beta2gamma2L GABA(A) receptors. GABA-gated chloride currents were measured using the two-electrode voltage-clamp technique. The peak amplitude of GABA-gated chloride currents was reduced by the PKC activator phorbol 12-myristate 13-acetate (PMA), but not by the inactive analog phorbol 12-mono-myristate (PMM). This effect of PMA was inhibited by the protein kinase inhibitor staurosporine. To investigate whether the activation of PKC could alter neurosteroid modulation of the GABA(A) receptor, the effect of PMA was studied on the positive allosteric modulatory steroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (THDOC) and the negative modulatory neurosteroid pregnenolone sulfate (PS). THDOC potentiation of GABA-gated chloride currents was found to be increased by approximately 120% following PMA treatment, while PS inhibition was not affected. The increase in THDOC potentiation by PMA was blocked by staurosporine. No change in THDOC potentiation was observed following PMM treatment. The enhancement of THDOC potentiation following PMA treatment was not due to a shift in the GABA EC50. In addition to inhibiting the peak amplitude of the GABA response, PMA treatment resulted in non-desensitizing GABA responses. Similarly, GABA responses of receptors which had been desensitized with prolonged GABA application also showed a reduction in peak amplitude and reduced desensitization. THDOC potentiation of desensitized receptors was enhanced approximately 70% with respect to non-desensitized receptors. The present results demonstrate that protein phosphorylation and receptor desensitization alter modulation of the GABA(A) receptor complex by some neurosteroids.
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PMID:Effects of PKC activation and receptor desensitization on neurosteroid modulation of GABA(A) receptors. 949 38

Nitric oxide (NO) is thought to play an essential role in neuronal processing, but the downstream mechanisms of its action remain unclear. We report here that NO analogs reduce GABA-gated currents in cultured retinal amacrine cells via two distinct, but convergent, cGMP-dependent pathways. Either extracellular application of the NO-mimetic S-nitroso-N-acetyl-penicillamine (SNAP) or intracellular perfusion with cGMP depressed GABA currents. This depression was partially blocked by a pseudosubstrate peptide inhibitor of cGMP-dependent protein kinase (PKG), suggesting both PKG-dependent and independent actions of cGMP. cAMP-dependent protein kinase (PKA) is known to enhance retinal GABA responses. 8-Bromoinosine 3',5'-cyclic monophosphate (8Br-cIMP), which activates a type of cGMP-stimulated phosphodiesterase that hydrolyzes cAMP, also significantly reduced GABA currents. 1-Methyl-3-isobutylxanthine (IBMX), a nonspecific phosphodiesterase (PDE) inhibitor, blocked both the action of 8Br-cIMP and the portion of SNAP-induced depression that was not blocked by PKG inhibition. Our results suggest that NO depresses retinal GABAA receptor function by simultaneously upregulating PKG and downregulating PKA.
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PMID:Nitric oxide depresses GABAA receptor function via coactivation of cGMP-dependent kinase and phosphodiesterase. 950 95

The role of protein kinase A (PKA) and protein kinase C (PKC) in the function and modulation by mercury chloride of the GABA(A) receptor-chloride channel complex was studied with rat dorsal root ganglion cells using the whole-cell patch clamp technique. When added to the internal pipette solutions, both KT 5720, a selective PKA inhibitor, and calphostin C, a selective PKC inhibitor, increased the maximal current and shifted the EC50 for GABA in the direction of higher GABA concentrations. GABA-activated currents were decreased by the addition of 5 mM cAMP to the internal pipette solution, and by external perfusion of 100 nM phorbol 13-myristate 13-acetate. Mercury chloride potentiation of GABA-activated currents was blocked by internal application of 5 mM cAMP. PKA in the recording pipette abolished the mercury chloride potentiation of GABA-activated currents. In contrast, 0.56 microM KT 5720, but not calphostin C, in the internal pipette solution enhanced the effect of mercury chloride. In conclusion, both PKA and PKC negatively regulate the activity of the GABA(A) receptor-channel complex probably through phosphorylation of the receptor, and the PKA system underlies the mechanism of mercury chloride potentiation of GABA-activated currents.
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PMID:The role of phosphorylation in the activity and mercury modulation of GABA-induced currents in rat neurons. 951 34


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