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)

Studies of various forms of synaptic plasticity in the central nervous system have provided insights into the cellular and molecular mechanisms for certain types of learning and memory. Activity-induced decreases and increases in synaptic efficacy can be elicited in mammalian neurons. Long-term depression (LTD) and long-term potentiation (LTP) are two major forms of activity-dependent synaptic plasticity in the brain. LTD of excitatory synaptic transmission in the cerebellum in the most well studied form of synaptic depression. The induction of cerebellar LTD requires conjunctive activation of alpha-amino-3-hydroxy-5-methyl-4-isoxalepropionate (AMPA) receptors, metabotropic glutamate receptors (mGluRs) and L-type voltage-dependent Ca2+ channels. Several intracellular second messengers and protein kinases are critical for cerebellar LTD, including cGMP, cGMP-dependent protein kinase and protein kinase C (PKC). A novel intercellular messenger, nitric oxide (NO), is found in the cerebellum, is released durinng synaptic stimulation, and may contribute to cerebellar LTD. The expression of cerebellar LTD is mediated by postsynaptic desensitization of AMPA receptors. Recently, a form of homosynaptic LTD has been described in the CA1 region of the hippocampus. The induction of hippocampal LTD is postsynaptic. N-Methyl-D-aspartate receptors and mGluRs are important for induction of hippocampal LTD. Other intracellular and intercellular messengers, such as NO, cGMP and cAMP, might act downstream from glutamate receptors during hippocampal LTD. The expression of hippocampal LTD is likely to be in part presynaptic. While cerebellar LTD may be important for motor learning, the behavioral role of hippocampal LTD remains to be explored.
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PMID:Long-term depression: a learning-related type of synaptic plasticity in the mammalian central nervous system. 871 37

1. The effects of dopamine on the slow Ca(2+)-dependent K+ current (IAHP; AHP, afterhyperpolarization) and spike frequency adaptation were studied by whole cell voltage-clamp and sharp microelectrode current-clamp recordings in rat CA1 pyramidal neurons in rat hippocampal slices. 2. Dopamine suppressed IAHP in a dose-dependent manner, under whole cell voltage-clamp conditions. Similarly, under current-clamp conditions, dopamine inhibited spike frequency adaptation and suppressed the slow afterhyperpolarization. 3. The effect of dopamine on IAHP was mimicked by a D1 receptor agonist and blocked by dopamine receptor antagonists only in a minority of the cells. 4. Dopamine suppressed IAHP after blocking or desensitizing the beta-adrenergic receptors and, hence, did not act by cross-reacting with this receptor type. 5. The effects of dopamine on IAHP and spike frequency adaptation were suppressed by blocking the adenosine 3',5'-cyclic monophosphate (cAMP)-dependent kinase (PKA) with Rp-cAMPS and, hence, are probably mediated by the activation of this kinase. 6. We conclude that dopamine increases hippocampal neuron excitability, like other monoamine neurotransmitters, by suppressing IAHP and spike frequency adaptation, via cAMP and protein kinase A. The receptor type mediating this effect of dopamine remains to be defined.
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PMID:Dopamine modulates the slow Ca(2+)-activated K+ current IAHP via cyclic AMP-dependent protein kinase in hippocampal neurons. 874 30

Long-term potentiation (LTP) and long-term depression (LTD) are persistent modifications of synaptic efficacy that may contribute to information storage in the CA1 region of the hippocampus. Persistently enhanced phosphorylation has been implicated in the maintenance phase of LTP. This hypothesis is supported by our previous observation that protein kinase M zeta (PKM zeta), the constitutively active catalytic fragment of a single protein kinase C isoform (PKC zeta), increases in LTP maintenance. In contrast, dephosphorylation may be important in LTD maintenance, because phosphatase inhibitors reverse established LTD, in addition to blocking its induction. Because phosphorylation is determined by a balance of phosphatases and kinases, both increases in phosphatase activity and decreases in kinase activity could contribute to LTD. We now report that the reduction of protein kinase activity by H7, as well as selective inhibition of PKC by chelerythrine, mimics and occludes the maintenance phase of homosynaptic LTD in rat hippocampal slices. Conversely, saturated LTD occludes the synaptic depression caused by chelerythrine. Biochemical analysis demonstrates a decrease of PKM zeta, as well as PKCs gamma and epsilon, in LTD maintenance and a concomitant loss of constitutive PKC activity. LTD and the downregulation of PKM zeta are prevented by NMDA receptor antagonists and Ca(2+)-dependent protease inhibitors. Both LTD and the downregulation of PKM zeta are reversible by high-frequency afferent stimulation. Our findings indicate that the molecular mechanisms of LTP and LTD maintenance are inversely related through the bidirectional regulation of PKC.
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PMID:Bidirectional regulation of protein kinase M zeta in the maintenance of long-term potentiation and long-term depression. 875 45

Muscarinic, cholinergic inputs, largely from the medial septum, have pronounced effects on hippocampal cell excitability. A major effect of synaptically released ACh is block of the slow Ca(2+)-dependent potassium current, called IAHP. Protein kinase C exists in the hippocampus in high concentrations, its activation blocks IAHP, and it has been suggested as a mediator of the muscarinic-receptor-(mAChR)-mediated actions. Using conditions that produce a stable postspike afterhyperpolarizing current (IAHP) in whole-cell recordings from CA1 hippocampal pyramidal neurons in the slice preparation, we have investigated the role of PKC in the cholinergic inhibition of IAHP mediated by mACHRs. Bath application of the general kinase inhibitor, H7, had no effect on inhibition of IAHP by carbachol, although H7 dramatically reduced inhibition of IAHP by the phorbol ester, phorbol-12, 13-diacetate (PDA). Another muscarinic response thought to be mediated by PKC-inhibition of GABAB-mediated hyperpolarization-was reduced by extracellular H7 treatment, suggesting that the coupling between mAChRs and protein kinase activity was maintained in whole-cell recordings. We also discovered that PDA does not mediate its effects on IAHP directly. Intracellular perfusion of high concentrations of H7 (10 mM) or the specific PKC inhibitor, PKCI(19-31) (1 mM), did not prevent inhibition of IAHP by PDA. These results are consistent with an indirect, presynaptic action of phorbol esters on IAHP, possibly mediated through enhanced release of neurotransmitter from surrounding cells.
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PMID:Whole-cell voltage-clamp investigation of the role of PKC in muscarinic inhibition of IAHP in rat CA1 hippocampal neurons. 879 18

Both the atriopeptides and nitric oxide act in the nervous system by activating guanylyl cyclases to stimulate the production of cyclic GMP. Thus a key to understanding the roles of these messengers is to understand the functions of cyclic GMP in the nervous system. Three potential targets for cyclic GMP have been identified, phosphodiesterases, protein kinases and ion channels. In this study we describe a method using autoradiography to localize specific [3H]-cGMP binding sites in the brain. The specific binding of [3H]-cGMP to rat brain sections was saturable (Bmax = 1.5 pmol/mg protein) and of high affinity (KD = 164 nM). The pharmacological characteristics were consistent with binding to the cGMP-dependent protein kinase. Highest densities of binding were seen in the medial habenula, basal ganglia, locus ceruleus and nucleus of the solitary tract. The CA1 pyramidal cells of the hippocampus, the neocortex, thalamus and cerebellum were also labelled. This method should prove useful in studies of potential targets for cyclic GMP in the brain.
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PMID:Autoradiographic localization of [3H]-cyclic GMP binding sites in the rat brain. 881 19

Cyclic nucleotide-gated (CNG) channels are Ca(2+)-permeable, nonspecific cation channels that can be activated through direct interaction with cAMP and/or cGMP. Recent electrophysiological evidence for these channels in cultured hippocampal neurons prompted us to investigate the expression of CNG channel genes in hippocampus. PCR amplification detected the expression of transcripts for subunit 1 of both the rod photoreceptor (RCNGC1) and the olfactory receptor cell (OCNGC1) subtype of CNG channel in adult rat hippocampus. In situ hybridization detected expression of both channel subtypes in most principal neurons, including pyramidal cells of the CA1 through CA3 regions and granule cells of the dentate gyrus. From the hybridization patterns, we conclude that the two genes are colocalized in individual neurons. Comparison of the patterns of expression of type 1 cGMP-dependent protein kinase and the CNG channels suggests that hippocampal neurons can respond to changes in cGMP levels with both rapid changes in CNG channel activity and slower changes induced by phosphorylation. Future models of hippocampal function should include CNG channels and their effects on both electrical responses and intracellular Ca2+ levels.
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PMID:Rat hippocampal neurons express genes for both rod retinal and olfactory cyclic nucleotide-gated channels: novel targets for cAMP/cGMP function. 881 19

During transient cerebral ischemia, intracellular calcium increases initiating a cascade of events which leads to the delayed death of neurons located in the hippocampus. Coupled to this calcium disturbance is the rapid decrease of calcium/calmodulin kinase II (CaM kinase) activity, a protein kinase critical to neuronal functioning. The present study correlated the increased locomotor activity following ischemic insult with alterations in CaM kinase mRNA levels and immunocytochemical labeling of alpha and beta CaM kinase subunits in the hippocampus. The protective effect of hypothermia was also compared with CaM kinase mRNA levels and immunoreactivity. Levels of CaM kinase message for either alpha or beta subunits was not altered in ischemic gerbils compared to sham or hypothermic ischemic conditions. Immunoreactivity for both the alpha and beta subunits was markedly reduced in the vulnerable CA1 region of ischemic animals compared to sham controls. Gerbils that underwent the ischemic insult while hypothermic showed no decrement in staining. CaM kinase-like immunoreactivity in the ischemia-resistant CA3 sector was not altered following ischemia. These data suggest that the loss of hippocampal CaM kinase immunoreactivity observed at 24 h following ischemia is not associated with a reduction in CaM kinase mRNA levels and support the notion that the rapid decline in CaM kinase activity following ischemic insult is a result of a posttranslational modification and/or translocation of the enzyme.
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PMID:Transient cerebral ischemia decreases calcium/calmodulin-dependent protein kinase II immunoreactivity, but not mRNA levels in the gerbil hippocampus. 882 62

Platelet-derived growth factor (PDGF) and PDGF receptors (PDGFRs) are ubiquitously expressed in the mammalian central nervous system, where they exert trophic actions on both neuronal and glial cells. However, the acute actions of PDGF on synaptic transmission are unknown. We report a novel regulatory action of PDGF/PDGFR. Activation of PDGFRs inhibited the function of native type A gamma-aminobutyric acid (GABAA) receptors (GABAA-RS) in rat hippocampal CA1 pyramidal neurons and mouse brain membrane vesicles. The mechanism of this inhibition was studied with a panel of mutant PDGFRS-beta coexpressed with cloned human GABAA-Rs in Xenopus oocytes. These experiments revealed that phospholipase C-gamma is the protein that relays the inhibitory signal from PDGFRS to GABAA-Rs. Experiments with microinjected EGTA and inositol-1, 3, 4-triphosphate demonstrated that inhibition of GABAA-Rs depended on a phospholipase C-gamma-mediated increase in intracellular Ca(2+)-levels. The PDGFR-induced inhibitory effect was independent of the subunit composition of GABAA-RS. Moreover, GABAA-RS composed of alpha 1 beta 1 S409A subunits, which do not contain any known protein kinase C phosphorylation sites, were inhibited by PDGF to the same extent as wild-type GABAA-RS. Inhibitors of protein kinase C, CA2+/calmodulin-dependent protein kinase II, calcineurin, and tyrosine phosphatases did not affect the modulatory actions of PDGFR. In conclusion, our results suggest that PDGFRs exert potent modulatory actions on GABAA-R-dependent inhibitory synaptic transmission. These regulatory actions of PDGF could play important roles in the function of the mammalian central nervous system during physiological and pathophysiological conditions.
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PMID:Platelet-derived growth factor receptor is a novel modulator of type A gamma-aminobutyric acid-gated ion channels. 884 10

1. The effects of the selective thromboxane A2 (TXA2) receptor agonist I-BOP on neuronal excitability and synaptic transmission were studied in the CAl neurones of rat hippocampal slices by an intracellular recording technique. 2. Superfusion of I-BOP (0.5 microM) resulted in a biphasic change of the excitatory postsynaptic potential (e.p.s.p.), which was blocked by pretreatment with SQ 29548, a specific antagonist of TXA2 receptors. The inhibitory phase of I-BOP on the e.p.s.p. was accompanied by a decrease in neuronal membrane input resistance. 3. The sensitivity of postsynaptic neurones to glutamate receptor agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or N-methyl-D-aspartate (NMDA), was unchanged by I-BOP (0.5 microM) pretreatment. 4. Bath application of Ba2+ (0.5 mM) prevented both the I-BOP-induced reduction of the neuronal membrane input resistance and the blockade of e.p.s.p. induced by I-BOP. 5. Intracellular dialysis of the hippocampal CA1 neurones with GDP (10 mM) significantly attenuated the I-BOP inhibition of e.p.s.p. and membrane input resistance. Incubation of the slices with either pertussis toxin (PTX, 5 micrograms ml-1 for 12 h) or cholera toxin (CTX, 5 micrograms ml-1 for 12 h) did not affect the biphasic action of I-BOP on the e.p.s.p. or the reduction of membrane input resistance induced by I-BOP. 6. Pretreatment of the slices with the protein kinase C (PKC) inhibitor, NPC-15437 (20 microM), abolished the biphasic modulation by I-BOP (0.5 microM) of the e.p.s.p. Intracellular application of a specific PKC inhibitor, PKCI 19-36 (20 microM), completely inhibited the I-BOP reduction of e.p.s.p. The specific cyclic AMP-dependent protein kinase (PKA) inhibitor, Rp-cyclic adenosine 3',5'-monophosphate (Rp-cyclic AMPS, 25 microM), had no effect on the I-BOP action. 7. In this study we have demonstrated, for the first time, the existence of functional TXA2 receptors in the hippocampus which mediate the effects of a TXA2 agonist on neuronal excitability and synaptic transmission. Activation of the presynaptic TXA2 receptors may stimulate the release of glutamate. Conversely, activation of postsynaptic TXA2 receptors leads to inhibition of synaptic transmission resulting from a decrease in the membrane input resistance of the neurones. The pre- and postsynaptic actions of the TXA2 agonist are both mediated by PTX- and CTX-insensitive G-protein-coupled activation of PKC pathways.
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PMID:Thromboxane A2 agonist modulation of excitatory synaptic transmission in the rat hippocampal slice. 886 65

1. The effect of dopamine (DA) on the excitatory synaptic transmission was studied in the CA1 neurons of rat hippocampal slices using intracellular recording technique. 2. Depolarizing excitatory postsynaptic potentials (EPSPs) were evoked by stimulation of the Schaffer collateral-commissural pathway. Superfusion of DA (0.03-1 microM) reversibly decreased the EPSP in a concentration-dependent manner and with an estimated IC50 of 0.3 microM. The sensitivity of postsynaptic neurons to the glutamate-receptor agonists, alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid or N-methyl-D-aspartate was unchanged by DA (0.3 microM) pretreatment. In addition, DA (0.3 microM) increased the magnitude of paired-pulse facilitation, a phenomenon attributed to an increase in the amount of transmitter released in response to the second stimulus. 3. The reduction of DA (0.3 microM) on the EPSP was antagonized by sulpiride (1-10 nM), a selective D2-receptor antagonist. However, D1-receptor antagonist, SKF-83566 (1-10 microM), did not significantly affect the reduction of DA (0.3 microM) on the EPSP. 4. (+/-)-2-(N-Phenylethyl-N-propyl)amino-5-hydroxytetralin (1 microM), an agonist of D2 receptor, mimicked the inhibitory effect of DA on the EPSP. However, neither the D1-receptor agonist SKF-38393 (1 microM) nor the D3-receptor agonist (PD-128,907 (1 microM) affected the EPSP. 5. Incubation of hippocampal slices with pertussis toxin (PTX, 5 micrograms/ml) for 12 h prevented the reduction of EPSP induced by DA (0.3 microM). 6. Rp-adenosine-3',5'-cyclic monophosphothioate (25 microM), a potent inhibitor of protein kinase A (PKA), alone decreased the amplitude of EPSP below baseline values and prevented the subsequent reduction by DA (0.3 microM). 7. These results indicate that DA at a low concentration (< or = 0.3 microM) reduces the excitatory response of hippocampal CA1 neurons after synaptic stimulation via the activation of presynaptic D2 receptors. The presynaptic action of DA is mediated by a PTX-sensitive Gi-proteins-coupled to PKA pathway.
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PMID:Characterization of dopamine receptors mediating inhibition of excitatory synaptic transmission in the rat hippocampal slice. 889 Mar 1


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