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)

Memory storage consists of a short-term phase that is independent of new protein synthesis and a long-term phase that requires the synthesis of new proteins and RNA. A cellular representation of these two phases has been demonstrated recently for long-term potentiation (LTP) in both the Schaffer collateral and the mossy fibers of the hippocampus, a structure widely thought to contribute to memory consolidation. By contrast, much less information is available about the medial perforant pathway (MPP), one of the major inputs to the hippocampus. We found that both a short-lasting and a long-lasting potentiation (L-LTP) can be induced in the MPP of rat hippocampal slices by applying repeated tetanization in reduced levels of magnesium. This potentiation was dependent on the activation of NMDA receptors. The early, transient phase of LTP in the MPP did not require either protein or RNA synthesis, and it was independent of protein kinase A activation. By contrast, L-LTP required the synthesis of proteins and RNA, and was selectively blocked by inhibitors of cAMP-dependent protein kinase (PKA). Forskolin, an adenylate cyclase activator, also induced a L-LTP that was attenuated by inhibition of transcription. Our results demonstrate that, like LTP in the Schaffer collateral and mossy fiber pathways, MPP LTP also consists of a late phase that is dependent on protein and RNA synthesis and PKA activity. Thus, cAMP-mediated transcription appears to be a common mechanism for the late form of LTP in all three pathways within the hippocampus.
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PMID:A macromolecular synthesis-dependent late phase of long-term potentiation requiring cAMP in the medial perforant pathway of rat hippocampal slices. 862 57

The mechanisms responsible for protein kinase-c (PKC) mediated potentiation of NMDA receptors are poorly understood. One hypothesis is that PKC-activation reduces the receptor's characteristic voltage-dependent Mg(2+)-blockade. Experiments performed on Xenopus oocytes expressing cloned NMDA receptors demonstrated that PKC-activation induced no change in the sensitivity of zeta 1/epsilon 3 and zeta 1/epsilon 4 receptors to Mg(2+)-blockade and, even though PKC-activation did induce a small shift in Mg2+ sensitivity for the zeta 1/epsilon 1 and zeta 1/epsilon 2 receptors, the change seen was not large enough to account for an appreciable increase in NMDA receptor activity. Baseline Mg(2+)-sensitivities and levels of PKC-mediated potentiation were also quantified for each of the di-heteromeric NMDA receptors. The order of Mg(2+)-sensitivity is zeta 1/epsilon 1 (most sensitive) > zeta 1/epsilon 2 > zeta 1/epsilon 4 > zeta 1/epsilon 3 (least sensitive). PKC-activation caused a 2-fold increase in zeta 1/epsilon 1 currents, a 4-fold increase in zeta 1/epsilon 2 currents and no change in either zeta 1/epsilon 3 or zeta 1/epsilon 4 currents. These data suggest that PKC-potentiation of the cloned di-heteromeric NMDA receptors does not involve a reduction in Mg(2+)-blockade. The di-heteromeric receptors possess varied properties in regard to PKC-potentiation and Mg(2+)-blockade which have been quantified here.
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PMID:Effect of protein kinase-C activation on the Mg(2+)-sensitivity of cloned NMDA receptors. 868 94

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

To identify the protein kinases regulating synaptic NMDA receptors, as well as the conditions favoring enhancement of NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) by phosphorylation, we studied the effects of kinase activation and inhibition in hippocampal neurons. Inhibition of cAMP-dependent protein kinase (PKA) prevented recovery of NMDA receptors from calcineurin-mediated dephosphorylation induced by synaptic activity, suggesting that tonically active PKA phosphorylates receptors during quiescent periods. Conversely, elevation of PKA activity by forskolin, cAMP analogs, or the beta-adrenergic receptor agonists norepinephrine and isoproterenol overcame the ability of calcineurin to depress the amplitude of NMDA EPSCs. Thus, stimulation of beta-adrenergic receptors during excitatory synaptic transmission can increase charge transfer and Ca2+ influx through NMDA receptors.
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PMID:Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. 878 56

Four splice variants of the NR1 receptor subunit, characterized by the presence or absence of cassettes encoding inserts of 21 (Insert 1) and 37 (Insert 2) amino acids were expressed in Xenopus oocytes and studied using voltage-clamp techniques. In 1.8 mM Ca2+, a slow inward current (Islow), which peaked 20 s after exposure to NMDA was evident when Insert I was present, but not when absent. However, in elevated external Ca2+ medium a similar Islow was observed in variants missing Insert I. The Ca2+ dependency of Islow reflected a requirement for intracellular accumulation of Ca2+. The divalent ion permeability of Insert I containing and Insert 1 lacking receptor channels expressed alone, as well as in heteromeric assemblies with NR2A and NR2B, was similar for all combinations tested. Thus, the lower Ca2+ dependency for Islow in oocytes expressing Insert I was not due to higher calcium entry. Islow was less sensitive to blockers of ICl(Ca) than were endogenous calcium-activated chloride currents (ICl(Ca)). Also, Islow was not abolished in Cl(-)-free external medium, when voltage was manipulated such that Islow was outward-going. Thus, Islow, while containing a component due to activation of endogenous ICl(Ca), is primarily due to current flowing through the receptor ion channel. Development of Islow was unaffected by PKC or PKA inhibitors. The modulation of the Ca2+ dependency of Islow by Insert I occurs in a range of Ca2+ concentrations which are physiologically relevant, and may provide an important means of modulation of glutamate transmission under normal and pathological conditions.
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PMID:Alternative splicing of the NMDAR1 subunit affects modulation by calcium. 880 18

In previous studies, we have demonstrated that chronic administration of morphine or cocaine produces some common biochemical adaptations in the ventral tegmental area (VTA) and nucleus accumbens (NAc), components of the mesolimbic dopamine system implicated in the reinforcing actions of these and other drugs of abuse. Since this neural pathway is also implicated in the reinforcing actions of ethanol, it was of interest to determine whether chronic ethanol exposure results in similar biochemical adaptations. Indeed, as seen for chronic morphine and cocaine treatments, we show here that chronic ethanol treatment increased levels of tyrosine hydroxylase and glial fibrillary acidic protein immunoreactivity, and decreases levels of neurofilament protein immunoreactivity, in the VTA. Also like morphine and cocaine, ethanol increases levels of cyclic AMP-dependent protein kinase activity in the NAc. These actions of ethanol required long-term exposure to the drug, and were in most cases not seen in the substantia nigra or caudateputamen, components of the nigrostriatal dopamine system studied for comparison. Altered levels of tyrosine hydroxylase in catecholaminergic cells frequently reflect altered states of activation of the cells. Moreover, increasing evidence indicates that ethanol produces many of its acute effects on the brain by regulating NMDA glutamate and GABAA receptors. We therefore examined the influence of chronic ethanol treatment on levels of expression of specific glutamate and GABA receptor subunits in the VTA. It was found that long-term, but not short-term, ethanol exposure increased levels of immunoreactivity of the NMDAR1 subunit, an obligatory component of NMDA glutamate receptors, and of the GluR1 subunit, a component of many AMPA glutamate receptors; but at the same time, long-term ethanol exposure decreased immunoreactivity levels of the alpha 1 subunit of the GABAA receptor complex. These changes are consistent with an increased state of activation of VTA neurons inferred from the observed increase in tyrosine hydroxylase (TH) expression. These results demonstrate that chronic ethanol exposure results in several biochemical adaptations in the mesolimbic dopamine system, which may underlie prominent changes in the structural and functional properties of this neural pathway related to alcohol abuse and alcoholism.
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PMID:Biochemical actions of chronic ethanol exposure in the mesolimbic dopamine system. 886 59

Single electrode whole cell current- and voltage-clamp techniques in conjunction with intra- and extracellular phoresis and extracellular application of pharmacological agents were applied to study neurons in deep layers of the brainstem of anesthetized, paralyzed and artificially ventilated cats. We compared slow rhythmic changes and stimulus-evoked postsynaptic current and voltage responses of neurons as they were recorded with fine-tipped microelectrodes filled with 2-3 M 'microelectrode solutions' or with 0.3 M 'patch solutions', or with patch electrodes. The experimental data were then compared with the effects of somatic and dendritic conductance changes simulated in a cell model. A new method was introduced for alternating current and voltage-clamp measurements performed at 300 Hz, which provided quasi-simultaneous measurements of slow changes of spontaneous synaptic currents and potentials. During current or voltage clamp, chemicals which affect voltage- and receptor-controlled conductances were ionophoresed intracellularly through single or theta-type glass electrodes. We show examples of activation of low-voltage activated Ca2+ responses after blockade of Na+ currents by intracellular QX 314 and K+ currents by intracellular Cs+ injections in addition to Sp-cAMPs to activate protein kinase A. TEA, NMDA and GABA were used to demonstrate the effectiveness of extracellular application of drugs through multibarrel electrodes or local application through a 'bath'. The various tests demonstrated that single electrode whole cell current- and voltage-clamp methods, in combination with various techniques for drug application, can be well applied to study the biophysical properties and pharmacological sensitivities of neurons embedded in in vivo networks within deep layers of the brain.
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PMID:Voltage-clamp analysis of neurons within deep layers of the brain. 887 77

Dynamic regulation of ion channel interactions with the cytoskeleton mediates aspects of synaptic plasticity, yet mechanisms for this process are largely unknown. Here, we report that two inwardly rectifying K+ channels, Kir 2.1 and 2.3, bind to PSD-95, a cytoskeletal protein of postsynaptic densities that clusters NMDA receptors and voltage-dependent K+ channels. Kir 2.3 colocalizes with PSD-95 in neuronal populations in forebrain, and a PSD-95/Kir 2.3 complex occurs in hippocampus. Within the C-terminal tail of Kir 2.3, a serine residue critical for interaction with PSD-95, is also a substrate for phosphorylation by protein kinase A (PKA). Stimulation of PKA in intact cells causes rapid dissociation of the channel from PSD-95. This work identifies a physiological mechanism for regulating ion channel interactions with the postsynaptic density.
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PMID:Binding of the inward rectifier K+ channel Kir 2.3 to PSD-95 is regulated by protein kinase A phosphorylation. 889 15

Ion channels are ubiquitous membrane proteins that may be organized into different families according to their predicted transmembrane topology. They are concerned with rapid signalling over plasma and intracellular membranes and are activated, depending on their type, by transmembrane voltage, intracellular second messengers or extracellular neurotransmitters. Intracellular activities of protein kinases and phosphatases act to modulate ion channel activity. The modulation of the function of ligand activated, neuronal ion channels, that are crucial for synaptic transmission, may be an important basis for a modulation of a synaptic efficiency. The following review concentrates, due to space limitations, on the postranslational modification, and on the modulation of the function by protein kinase C and protein kinase A, of ligand-gated GABAA channels and NMDA channels on a molecular level.
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PMID:Functional modulation of ligand-gated GABAA and NMDA receptor channels by phosphorylation. 890 48

Somatostatin (SRIF) exerts a modulatory function on neuronal transmission in the CNS. It has been proposed that a reduction of calcium currents is the major determinant of the inhibitory activity of this peptide on synaptic transmission. Because the neurotoxicity induced by activation of the NMDA subtype of glutamate receptor is mediated through excessive Ca2+ influx, we investigated whether SRIF counteracted NMDA-induced neuronal cell death. Neurons from embryonic rat cerebral cortex were cultured for 7-10 days and then exposed to 0.5 and 1 mM NMDA for 24 h. The neuronal viability, as assessed by the colorimetric method, decreased by 40 and 60%, respectively, compared with the control condition. Morphological and biochemical evidence indicated that cell death occurred by necrosis and not through an apoptotic mechanism. SRIF (0.5-10 microM), simultaneously applied with excitatory amino acid, significantly reduced in a dose-dependent manner the neurotoxic effect of NMDA but not that of KA (0.25-0.5 mM). GABA (10 microM) partially protected neurons to a similar extent from NMDA- or KA-induced toxicity. SRIF type 2 receptor agonists, octreotide (SMS 201-995; 10 microM) and vapreotide (RC 160; 10 microM), did not influence the NMDA-dependent neurotoxicity. The intracellular mechanism involved in SRIF neuroprotection was investigated. Pertussin toxin (300 ng/ml), a G protein blocker, antagonized the protective effect of SRIF on NMDA neurotoxicity. Furthermore, the neuroprotective effect of SRIF was mimicked by dibutyryl-cyclic GMP (10 microM), a cyclic GMP analogue, whereas 8-(4-chlorphenylthio)-cyclic AMP (10 microM), a cyclic AMP analogue, was ineffective. The cyclic GMP content was increased in a dose-dependent manner by SRIF (2.5-10 microM). Finally, both specific (Rp-8-bromoguanosine 3',5'-monophosphate, 10 microM) and nonspecific [1-(5 isoquinolinylsulfonyl)-2-methylpiperazine (H7), 10 microM] cyclic GMP-dependent protein kinase (cGMP-PK) inhibitors did not interfere with NMDA toxicity but substantially reduced SRIF neuroprotection. Our data suggest a selective neuroprotective role of SRIF versus NMDA-induced nonapoptotic neuronal death in cortical cells. This effect is likely mediated by cGMP-PK presumably by regulation of the intracellular Ca2+ level.
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PMID:Neuroprotective effect of somatostatin on nonapoptotic NMDA-induced neuronal death: role of cyclic GMP. 897 41


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