Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine is known to be an important modulator of learning and memory processes, but its mechanisms of action at the cellular level are diverse and are not fully characterized. In the hippocampus, pharmacologically isolated monosynaptic IPSCs were measured using the whole-cell voltage-clamp recording technique. Both electrically evoked and spontaneous miniature GABA(A) receptor currents were recorded from CA1 pyramidal neurons in slices obtained from mature rats in the presence of the D3-selective agonist PD128907. The activation of D3 receptors inhibited synaptic GABAergic input without affecting presynaptic function or passive membrane properties. Inhibition of IPSCs evoked from stratum radiatum occurred via regulation of dynamin-dependent trafficking of the GABA(A) receptor, as inclusion of dynamin inhibitory peptide (50 microM) in the recording solution prevented the inhibitory effects of PD128907 (1 microM). This effect of D3 receptor activation could be prevented by intracellular application of either an inhibitor of protein kinase A (PKI, 20 microM) or an activator of protein kinase A (8-OH-cAMP, 50 microM). Neither synchronous IPSCs evoked from the stratum oriens nor asynchronous miniature IPSCs recorded from the stratum radiatum were affected by D3 agonist. The induction of long-term potentiation (LTP) of the extracellular field response in both the stratum radiatum and stratum oriens demonstrated that only potentiation in the stratum radiatum was significantly enhanced by PD128907 (1 microM). Our results suggest that the activation of D3 receptors can modulate GABA(A) receptor endocytosis in the hippocampus in a lamina specific manner, and thereby alter the efficacy of GABAergic transmission in the stratum radiatum of the CA1 region through a postsynaptic mechanism of action.
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PMID:Postsynaptic dopamine D3 receptor modulation of evoked IPSCs via GABA(A) receptor endocytosis in rat hippocampus. 1824 Mar 18

Synaptic plasticity has been studied extensively at excitatory synapses, whereas studies on plasticity at GABAergic inhibitory synapses have been limited. In the rat cerebellar cortex, postsynaptic depolarization of a Purkinje neuron (PN) induces long-term potentiation of GABA(A) receptor (GABA(A)R) responsiveness (termed rebound potentiation; RP). Induction of RP requires an increase in intracellular Ca(2+) concentration and resultant activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). We previously reported that GABA(B) receptor (GABA(B)R) activation coupled with depolarization suppresses RP induction by facilitating protein phosphatase 1 (PP-1)-mediated inhibition of CaMKII through down-regulation of cAMP-dependent protein kinase A (PKA) activity. Here, we examined the involvement of metabotropic glutamate receptor type 1 (mGluR1) in RP regulation. RP was monitored with the amplitudes of either the current responses to GABA or miniature inhibitory postsynaptic currents recorded from a PN in a primary culture or in a cerebellar slice. Inhibition of mGluR1 by an antagonist, 7(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate-ethyl-ester (CPCCOEt), prevented RP induction, which was abolished either by activation of adenylyl cyclase or by inhibition of PP-1. Furthermore, mGluR1 inhibition impaired depolarization-induced CaMKII activation. By contrast, activation of mGluR1 by the agonist (R,S)3,5-dihydroxyphenylglycine (DHPG) rescued RP induction from its suppression by GABA(B)R activation. The rescue was impaired either by inhibition of PKA or by facilitation of PP-1 activity. In addition, mGluR1 activation counteracted the GABA(B)R-mediated CaMKII inhibition. Taken together, these results suggest that mGluR1 activity counteracts GABA(B)R activity and contributes to RP induction through PKA activation, down-regulation of PP-1 and up-regulation of CaMKII.
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PMID:mGluR1-mediated facilitation of long-term potentiation at inhibitory synapses on a cerebellar Purkinje neuron. 1827 62

Noradrenergic modulation of cortical circuits is involved in information processing, regulation of higher functions, and prevention of epileptic activity. Here, we studied the effects of noradrenaline on the functional connectivity of GABAergic networks of the hippocampus and show that electrical synapses between interneurons are a novel target of noradrenergic modulation in vitro. Application of noradrenaline or of the selective beta-adrenergic agonist isoproterenol decreased gap junction-based coupling in paired recordings from stratum lacunosum-moleculare interneurons by approximately 40%. Similar results were obtained after pharmacological stimulation of the adenylyl cyclase with forskolin. In contrast, the adenylyl cyclase antagonist MDL12330A [cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine] or the specific protein kinase A (PKA) inhibitor H89 (N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride) enhanced the basal strength of coupling by approximately 30%. In addition, PKA-mediated phosphorylation was critical for both isoproterenol- and forskolin-dependent regulation of coupling, because inclusion of the PKA antagonist KT5720 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylicacid hexyl ester] in the recording pipettes prevented modulation. Lastly, we studied the effects of beta-adrenergic modulation on mixed polysynaptic transmission within the GABAergic network. Isoproterenol depressed propagation of GABA(A) receptor-mediated synaptic currents, but did not change significantly direct GABAergic input, indicating that regulation of electrical coupling adds flexibility to the information flow generated by chemical synapses. In conclusion, activation of beta-adrenergic receptors in stratum lacunosum-moleculare GABAergic networks reduces electrical synaptic transmission via a cAMP/PKA signaling cascade, and affects the degree of synaptic divergence within the circuit. We propose that this dynamic modulation and interplay between electrical and chemical synaptic transmission in GABAergic networks contributes to the tuning of memory processes in vivo, and prevents hypersynchronous activity.
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PMID:Noradrenergic modulation of electrical coupling in GABAergic networks of the hippocampus. 1828 97

Our previous study showed that intrathecal (i.t.) injection of platelet-activating factor (PAF) induced tactile allodynia, suggesting that spinal PAF is a mediator of neuropathic pain. The present study further examined the spinal molecules participating in PAF-induced tactile allodynia in mice. I.t. injection of L-arginine, NO donor (5-amino-3-morpholinyl-1,2,3-oxadiazolium (SIN-1) or 3,3-bis(aminoethyl)-1-hydroxy-2-oxo-1-triazene (NOC-18)) or cGMP analog (8-(4-chlorophenylthio)-guanosine 3',5'-cyclic monophosphate; pCPT-cGMP) induced tactile allodynia. PAF- and glutamate- but not SIN-1- or pCPT-cGMP-induced tactile allodynia was blocked by an NO synthase inhibitor. NO scavengers and guanylate cyclase inhibitors protected mice against the induction of allodynia by PAF, glutamate and SIN-1, but not by pCPT-cGMP. cGMP-dependent protein kinase (PKG) inhibitors blocked the allodynia induced by PAF, glutamate, SIN-1 and pCPT-cGMP. To identify signalling molecules through which PKG induces allodynia, glycine receptor alpha3 (GlyR alpha3) was knocked down by spinal transfection of siRNA for GlyR alpha3. A significant reduction of GlyR alpha3 expression in the spinal superficial layers of mice treated with GlyR alpha3 siRNA was confirmed by immunohistochemical and Western blotting analyses. Functional targeting of GlyR alpha3 was suggested by the loss of PGE(2)-induced thermal hyperalgesia and the enhancement of allodynia induced by bicuculline, a GABA(A) receptor antagonist in mice after GlyR alpha3 siRNA treatment. pCPT-cGMP, PAF, glutamate and SIN-1 all failed to induce allodynia after the knockdown of GlyR alpha3. These results suggest that the glutamate-NO-cGMP-PKG pathway in the spinal cord may be involved in the mechanism of PAF-induced tactile allodynia, and GlyR alpha3 could be a target molecule through which PKG induces allodynia.
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PMID:Glycinergic mediation of tactile allodynia induced by platelet-activating factor (PAF) through glutamate-NO-cyclic GMP signalling in spinal cord in mice. 1835 55

Cultured rat cortical astrocytes express two types of urotensin II (UII) binding sites: a high affinity site corresponding to the UT (GPR14) receptor and a low affinity site that has not been fully characterized. Activation of the high affinity site in astroglial cells stimulates polyphosphoinositide (PIP) turnover and provokes an increase in intracellular calcium concentration. We have hypothesized that the existence of distinct affinity sites for UII in rat cortical astrocytes could be accounted for by a possible cross-talk between UT and the ligand-gated ion channel GABA(A) receptor (GABA A R). Exposure of cultured astrocytes to UII provoked a bell-shaped increase in cAMP production, with an EC50 stimulating value of 0.83+/-0.04 pM, that was totally blocked in the presence of the adenylyl cyclase inhibitor SQ 22,536. In contrast, UII was found to inhibit forskolin-induced cAMP formation. In the presence of the specific PKA inhibitor H89, UII provoked a sustained stimulation of cAMP formation. Inhibition of PKA by H89 strongly reduced the stimulatory effect of UII on PIP metabolism. GABA and the GABA A R agonist isoguvacine provoked a marked inhibition of UII-induced cAMP synthesis and a significant reduction of UII-evoked PIP turnover. These data suggest that functional interaction between UT and GABA(A)R negatively regulates coupling of UT to the classical PLC/IP(3) signaling cascade as well as to the adenylyl cyclase/PKA pathway.
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PMID:Effect of GABA A receptor activation on UT-coupled signaling pathways in rat cortical astrocytes. 1835 46

Clinical observations and experimental studies have shown that hyperthermia can provoke febrile seizures, which are the most common type of pathological brain activity in children. We previously demonstrated that hyperthermia produced a depression of GABAergic neurotransmission in the hippocampus of immature rats in vitro. To investigate the possible mechanisms through which hyperthermia may modulate GABAergic neurotransmission in the hippocampus, whole-cell voltage clamp recordings were performed on CA1 pyramidal neurons in the immature rat brain slices. We found that hyperthermia (38.4-40 degrees C) when compared with baseline temperature of 32 degrees C reduced the frequency of both spontaneous inhibitory post-synaptic currents (sIPSCs) and miniature IPSCs (mIPSCs). Also, hyperthermia decreased the amplitudes of mIPSCs and reduced the mIPSC decay time constants and charge transfer. Non-stationary noise analysis of mIPSCs suggested that the number of open post-synaptic receptors but not single channel conductance was reduced during hyperthermia. Activation of adenylyl cyclase with forskolin prevented, whereas protein kinase A inhibitor N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide potentiated, the hyperthermia (40 degrees C)-induced depression of evoked IPSCs (evIPSCs). But protein kinase C activator phorbol 12, 13-dibutyrate (PDBu) did not significantly affect this depression of evIPSCs induced by hyperthermia. Furthermore, hyperthermia-induced depression of evIPSCs was attenuated by 4-aminopyridine, but not by BaCl(2). These results suggest that hyperthermia reduces GABA release from pre-synaptic terminals, in part by blocking the adenylyl cyclase-protein kinase A signaling pathway and activating pre-synaptic 4-aminopyridine-sensitive K(+) channels. Also, the changes in amplitude and decay time constant of the mIPSCs may suggest that hyperthermia also decreases post-synaptic GABA(A) receptor function.
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PMID:Mechanisms of hyperthermia-induced depression of GABAergic synaptic transmission in the immature rat hippocampus. 1864 87

Drugs of abuse usurp the mechanisms underlying synaptic plasticity in areas of the brain, a process that may contribute to the development of addiction. We previously reported that GABAergic synapses onto dopaminergic neurons in the ventral tegmental area (VTA) exhibit long-term potentiation (LTP(GABA)) blocked by in vivo exposure to morphine. The presynaptically maintained LTP requires the retrogradely released nitric oxide (NO) to activate a presynaptic cGMP signaling cascade. Previous work reported that inhibitory GABA(A) receptor synapses in the VTA are also potentiated by cAMP. Here, we explored the interactions between cGMP-dependent (PKG) and cAMP-dependent (PKA) protein kinases in the regulation of these GABAergic synapses and LTP(GABA). Activation of PKG was required for NO-cGMP signaling and was also essential for the induction of synaptically elicited LTP(GABA), but not for its maintenance. Synapses containing GABA(A) receptors were potentiated by NO-cGMP signaling, whereas synapses containing GABA(B) receptors on the same cells were not potentiated. Moreover, although the cAMP-PKA system potentiated GABA(A) synapses, synaptically induced LTP(GABA) was independent of PKA activation. Surprisingly, however, raising cGMP levels saturated potentiation of these synapses, precluding further potentiation by cAMP and suggesting a convergent end point for both signaling pathways in the regulation of GABAergic release. We further found that persistent GABAergic synaptic modifications observed with in vivo morphine did not involve the presynaptic cAMP-PKA cascade. Taken together, our data suggest a synapse-specific role for NO-cGMP-PKG signaling pathway in opioid-induced plasticity of VTA GABA(A) synapses.
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PMID:PKG and PKA signaling in LTP at GABAergic synapses. 1919 73

The wound-healing properties of honey are well established and it has been suggested that, among its pharmaco-active constituents, kynurenic acid (KA) exerts antinociceptive action on injured tissue by antagonizing NMDA at peripheral GABA receptors. The aim of this study was to investigate the quantitative profile of KA and of two recently identified, structurally related derivatives, 3-pyrrolidinyl-kynurenic acid (3-PKA) and its gamma-lactamic derivative (gamma-LACT-3-PKA), by examining their mass spectrometric behavior, in honeys from different botanical sources. We used a combination of HPLC-DAD-ESI-MS and NMR techniques (one-dimensional (1)H NMR and diffusion-ordered spectroscopy NMR). Chestnut honey constantly contained KA (2114.9-23 g/kg), 3-PKA (482.8-80 mg/kg) and gamma-LACT-3-PKA (845.8-32 mg/kg), confirming their reliability as markers of origin. A new metabolite, 4-quinolone (4-QUIN), was identified for the first time in one chestnut honey sample (743.4 mg/kg). Small amounts of KA were found in honeydew, sunflower, multifloral, almond and eucalyptus honeys, in the range of 23.1-143 mg/kg, suggesting contamination with chestnut honey. Total phenol content (TPC) was in the range from 194.9 to 1636.3 mg(GAE)/kg and total antiradical activity (TAA) from 61 to 940 mg/(GAE)/kg), depending on the botanical origin. Principal component analysis (PCA) was then done on these data. The three different clusters depicted: (i) antinociceptive activity from KA and/or its derivatives, typical of chestnut honey; (ii) antioxidant/radical scavenging activity by antioxidants responsible for the antiinflammatory action (dark honeys); (iii) peroxide-dependent antibacterial activity due to H(2)O(2) production by glucose oxidase in honey. The PCA findings provide useful indications for the dermatologist for the treatment of topical diseases, and the profiling of KA and its derivatives may shed light on new aspects of the kynurenine pathway involved in tryptophan metabolism.
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PMID:Quinoline alkaloids in honey: further analytical (HPLC-DAD-ESI-MS, multidimensional diffusion-ordered NMR spectroscopy), theoretical and chemometric studies. 1956 Mar 2

Depolarization of cerebellar granule cells in culture leads to up-regulation of the GABA(A) receptor delta subunit expression. To determine the signaling molecules involved, we examined the effects of protein kinase inhibitors and cyclic AMP-elevating compounds on basal and AMPAR agonist-induced delta mRNA expression in cerebellar granule cells. Treatment with the c-Jun N-terminal kinase (JNK) inhibitor SP600125 or with pituitary adenylate activating polypeptide increased delta subunit expression by 70%. Selective activation of AMPA receptors with CPW-399 also increased delta mRNA expression (2-4-fold). CPW-399 induction of delta subunit mRNA was reduced by prior treatment with either the MEK1/2 inhibitor U0126 or protein kinase A (PKA) inhibitors KT 5720 and H89. These effects were additive and combined treatment with U0126 and H89 completely prevented induction of delta subunit expression above basal levels. These results suggest that the role of JNK and ERK1/2/PKA on maintainence of delta subunit expression is diammetrically opposite. While JNK activity negatively regulates delta subunit mRNA expression in unstimulated neurons, activity of ERK1/2 and PKA are required for full induction of GABA(A) receptor delta subunit expression in response to AMPA receptor stimulation.
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PMID:AMPAR signaling mediating GABA(A)R delta subunit up-regulation in cultured mouse cerebellar granule cells. 2047 Aug 42

Our laboratory has recently demonstrated that an increase in the spinal neurosteroid, dehydroepiandrosterone sulfate (DHEAS) facilitates nociception via the activation of sigma-1 receptors and/or the allosteric inhibition GABA(A) receptors. Several lines of evidence have suggested that DHEAS positively modulates N-methyl-d-aspartate (NMDA) receptor activity within the central nervous system. Moreover, we have demonstrated that the activation of sigma-1 receptors increases NMDA receptor activity. Since NMDA receptors play a key role in the enhancement of pain perception, the present study was designed to determine whether spinally administered DHEAS modulates NMDA receptor-mediated nociceptive activity and whether this effect is mediated by sigma-1 or GABA(A) receptors. Intrathecal (i.t.) DHEAS was found to significantly potentiate i.t. NMDA-induced spontaneous pain behaviors. Subsequent immunohistochemical analysis demonstrated that i.t. DHEAS also increased protein kinase C (PKC)- and protein kinase A (PKA)-dependent phosphorylation of the NMDA receptor subunit NR1 (pNR1), which was used as a marker of NMDA receptor sensitization. The sigma-1 receptor antagonist, BD-1047, but not the GABA(A) receptor agonist, muscimol, dose-dependently suppressed DHEAS's facilitatory effect on NMDA-induced nociception and pNR1 expression. In addition, pretreatment with either a PKC or PKA blocker significantly reduced the facilitatory effect of DHEAS on NMDA-induced nociception. Conversely the GABA(A) receptor antagonist, bicuculline did not affect NMDA-induced pain behavior or pNR1 expression. The results of this study suggest that the DHEAS-induced enhancement of NMDA-mediated nociception is dependent on an increase in PKC- and PKA-dependent pNR1. Moreover, this effect of DHEAS on NMDA receptor activity is mediated by the activation of spinal sigma-1 receptors and not through the inhibition of GABA(A) receptors.
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PMID:An increase in spinal dehydroepiandrosterone sulfate (DHEAS) enhances NMDA-induced pain via phosphorylation of the NR1 subunit in mice: involvement of the sigma-1 receptor. 2060 Jan 71


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