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 tight-seal whole cell recording technique was used to study the effects of the metabotropic glutamate receptor (mGluR) agonist, trans-1-aminocyclopentane-1,3-dicarboxylic acid (t-ACPD) on spontaneous gamma-aminobutyric acid (GABA)-mediated synaptic currents in neonatal rat CA1 hippocampal neurons in slices obtained from postnatal (P) days P6-P12. 2. Bath application of t-ACPD (3-30 microM), in the presence of kynurenic acid, induced a concentration-dependent increase in frequency but not in amplitude of spontaneous GABAergic currents. The mean frequency ratio (t-ACPD 10 microM over control) was 2.6 +/- 1 (mean +/- SD), whereas the mean amplitude ratio was 1.1 +/- 0.3. 3. The effect of t-ACPD was partially antagonized by the mGluR antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG, 1 mM). 4. t-ACPD (10-30 microM) did not modify the frequency of miniature GABAergic synaptic currents recorded in tetrodotoxin (the mean frequency ratio of t-ACPD over control was 0.7 +/- 0.3). 5. Forskolin (30 microM), but not its analogue 1,9 dideoxyforskolin (30 microM), mimicked the effect of t-ACPD. Similar effects were obtained with 3-isobutyl-1-methylxanthine (IBMX, 200 microM). 6. The potentiating effect of t-ACPD on spontaneous GABAergic currents was prevented by Rp-cAMPS (30 microM), a specific antagonist of protein kinase A. This suggests that mGluRs localized at the soma-dendritic level of GABAergic interneurons and positively coupled to cyclic AMP may modulate GABA release during a critical period of postnatal development.
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PMID:Activation of metabotropic glutamate receptors increase the frequency of spontaneous GABAergic currents through protein kinase A in neonatal rat hippocampal neurons. 750 Jan 37

The cAMP-dependent protein kinase (PKA) has been shown to play an important role in long-term potentiation (LTP) in the hippocampus, but little is known about the function of PKA in long-term depression (LTD). We have combined pharmacologic and genetic approaches to demonstrate that PKA activity is required for both homosynaptic LTD and depotentiation and that a specific neuronal isoform of type I regulatory subunit (RI beta) is essential. Mice carrying a null mutation in the gene encoding RI beta were established by use of gene targeting in embryonic stem cells. Hippocampal slices from mutant mice show a severe deficit in LTD and depotentiation at the Schaffer collateral-CA1 synapse. This defect is also evident at the lateral perforant path-dentate granule cell synapse in RI beta mutant mice. Despite a compensatory increase in the related RI alpha protein and a lack of detectable changes in total PKA activity, the hippocampal function in these mice is not rescued, suggesting a unique role for RI beta. Since the late phase of CA1 LTP also requires PKA but is normal in RI beta mutant mice, our data further suggest that different forms of synaptic plasticity are likely to employ different combinations of regulatory and catalytic subunits.
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PMID:Hippocampal long-term depression and depotentiation are defective in mice carrying a targeted disruption of the gene encoding the RI beta subunit of cAMP-dependent protein kinase. 756 30

1. Recent evidence indicates that changes in the activity of cyclic AMP-dependent protein kinase may be involved in neuroadaptive mechanisms after chronic treatment with antidepressants. The aim of this study was to investigate the effect of repeated administration of fluoxetine (FL) and desipramine (DMI) on the distribution and activity of protein kinase C (PKC) in subcellular fractions of rat cortex (Cx) and hippocampus (Hc) under basal conditions and in response to a single in vivo administration of 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). 2. Rats were treated for 21 days with FL (5 mg kg-1 day-1, i.p.) or DMI (10 mg kg-1 day-1, i.p.). DOI was injected to groups of rats receiving repeated doses of antidepressants or to control rats 1 h before ex vivo PKC assay. Distribution of PKC was determined by [3H]-phorbol-12,13-dibutyrate ([3H]-PDBu) binding and PKC activity by the Amersham enzyme assay system. 3. Autoradiography of tissue sections revealed decreased [3H]-PDBu binding in CA1 region of hippocampus (by 18%) and paraventricular thalamic nucleus (by 28%) of rats after repeated administration of FL. 4. In vitro exposure of brain sections to 50 microM FL resulted in significant decreases (by 23-32%) of [3H]-PDBu binding in six out of seven regions examined; exposure to 100 microM FL reduced [3H]-PDBu binding (by 36-52%) in all regions. In contrast, exposure of brain sections to 100 microM DMI failed to alter specific [3H]-PDBu binding in brain sections. 5. The activity of PKC in subcellular fractions of Cx and Hc was significantly (by 40-50%) decreased in rats given repeated doses of FL or DMI. A single administration of either drug was without effect.6. A single in vivo administration of DOI to control rats resulted in reduced PKC activity (by 30-40%)in the particulate fraction of both Cx and Hc. This response to DOI was similar in DMI-treated rats but was not seen in rats given repeated doses of FL. A single administration of DOI to animals given repeated doses of FL resulted in PKC activities higher than those seen in rats treated with FL alone.7. The results indicate that repeated administration of FL and DMI produced similar changes in basal PKC activity but differentially affected the PKC response to the 5-HT2A/2c receptor agonist, DOI. The effect on basal PKC activity may result from a post-receptor action of antidepressants; the alteration of PKC response to DOI after fluoxetine could be due to receptor-mediated desensitization of the signalling system.
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PMID:Protein kinase C in rat brain cortex and hippocampus: effect of repeated administration of fluoxetine and desipramine. 758 77

Neuronal Cdc2-like kinase is a heterodimer of Cdk5 and a 25-kDa subunit that is derived from a 35-kDa brain- and neuron-specific protein called the neuronal Cdk5 activator (p35/p25nck5a) (Lew, J., Huang, Q.-Q., Qi, Z., Winkfein, R. J., Aebersold, R., Hunt, T., and Wang, J. H. (1994) Nature 371, 423-426; Tsai, L. H., Delalle, I., Caviness, V. S., Jr., Chae, T., and Harlow, E. (1994) Nature 371, 419-423). Upon screening of a human hippocampus library with a bovien Nck5a cDNA, we uncovered a distinct clone encoding a 39-kDa isoform of Nck5a. The isoform, designated the neuronal Cdk5 activator isoform (p39nck5ai), showed a high degree of sequence similarity to p35nck5a with 57% amino acid identity. Northern blot analysis detected its mRNA transcript in bovine and rat cerebrum and cerebellum, but not in any other rat tissues examined. In situ hybridization showed that Nck5ai was enriched in CA1 to CA3 of the hippocampus, but absent in the fimbria of hippocampal formation. Among seven cell lines in proliferating cultures, only PC12 and N2A, two cell lines capable of differentiating into neuron-like cells, were found to contain Nck5ai mRNA. A 30-kDa truncated form of Nck5ai expressed as a glutathione S-transferase fusion protein in Escherichia coli] was found to associate with Cdk5 to form an active Cdk5 kinase. Thus, the isoform shares many common characteristics with p35nck5a, including Ckd5 activating activity and brain- and neuron-specific expression. Both proteins show limited sequence homology to cyclins, suggesting that they define a new family of cyclin-dependent kinase-activating proteins.
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PMID:An isoform of the neuronal cyclin-dependent kinase 5 (Cdk5) activator. 759 34

The mechanism of ATP-induced long-term potentiation was studied pharmacologically using guinea-pig hippocampal slices. Application of 1-10 microM ATP for 10 min transiently depressed and then slowly augmented the synaptic transmission in CA1 neurons leading to long-term potentiation (LTP). This ATP-induced LTP was blocked by the addition of K-252b, an ecto-protein kinase inhibitor, but was enhanced by the addition of RK682, an ecto-phosphatase inhibitor, both of which do not permeate the cell membrane. These results suggest that ATP applied to the perfusate provides enough substrate for ecto-protein kinase to induce LTP through phosphorylation of extracellular domains of membrane proteins in CA1 neurons.
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PMID:The mechanism of ATP-induced long-term potentiation involves extracellular phosphorylation of membrane proteins in guinea-pig hippocampal CA1 neurons. 778 59

The involvement of ecto-protein kinase activity in activity-dependent long-term potentiation (LTP) was studied in CA1 neurons of guinea-pig hippocampal slices. Application of 5 microM K-252b, an ecto-protein kinase inhibitor, blocked LTP induced by a theta-burst stimulation (3 bursts composed of 5 pulses at 100 Hz with inter-burst intervals of 200 ms). On the other hand, under 10 microM RK682, an ecto-phosphatase inhibitor, a robust LTP was induced by a weak theta-burst stimulation (3 bursts composed of 3 pulses) which was just at the threshold for the induction of LTP in the control perfusate. These findings suggest that ATP released from presynaptic terminals during the burst stimulation plays an important role in the induction of LTP through phosphorylation of extracellular domains of synaptic membrane proteins, as the substrate for ecto-protein kinase.
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PMID:Extracellular phosphorylation of membrane protein modifies theta burst-induced long-term potentiation in CA1 neurons of guinea-pig hippocampal slices. 778 60

1. Previous studies have shown that beta-adrenergic receptor activation has many effects on neuronal function in hippocampal area CA1. However, all of the physiological effects of beta-adrenergic receptor activation in this region reported to date have been attributed to postsynaptic mechanisms. A series of studies was performed to test the hypothesis that beta-adrenergic receptor activation also acts presynaptically to enhance excitatory synaptic transmission. 2. Application of the selective beta-adrenergic agonist isoproterenol to hippocampal slices induced an increase in the amplitude of evoked excitatory postsynaptic currents (EPSCs) in CA1 pyramidal cells. This response was potentiated in the presence of a cyclic nucleotide phosphodiesterase inhibitor. Isoproterenol also resulted in the appearance of a late inward synaptic current that likely represents polysynaptically evoked EPSCs. Both the increased amplitude of the monosynaptic EPSC and the appearance of polysynaptic EPSCs in response to isoproterenol were blocked by H89, an inhibitor of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase. 3. Isoproterenol induced an increase in the frequency of spontaneous miniature EPSCs but did not affect the amplitude of these currents. In addition, isoproterenol had no effect on currents elicited by direct application of the ionotropic glutamate receptor agonist, (R,S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). 4. These results suggest that activation of presynaptic beta-adrenergic receptors enhances synaptic transmission in area CA1 via activation of cAMP-dependent protein kinase.
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PMID:Presynaptic enhancement of excitatory synaptic transmission by beta-adrenergic receptor activation. 780 26

Alterations in protein phosphorylation may be important in the pathogenesis of Alzheimer's disease and recent observations suggest that a subset of protein kinase pathways may be selectively altered. Calcium/calmodulin-dependent protein kinase II CaM kinase II) is the most abundant protein kinase in the brain and is believed to play an important role in the regulation of synaptic transmission, long-term potentiation and other forms of neuronal plasticity. We have now evaluated brains of individuals with Alzheimer's disease for changes in the distribution and density of immunoreactivity for the alpha subunit of CaM kinase II. CaM kinase II immunoreactivity was found in cytoarchitectural areas and neurons vulnerable to the formation of neurofibrillary angles and senile plaques. Over 80% of neurons bearing neurofibrillary tangles expressed CaM kinase II. Loss of CaM kinase II immunoreactivity was found in CA1, commensurate with neuronal loss in this area. Remaining CA1 neurons, however, had preserved CaM kinase II immunoreactivity. Preservation in the distribution and density of CaM kinase II immunoreactivity was observed in other hippocampal regions and in a multimodal association area, area 20. These results suggest CaM kinase II expression in the Alzheimer's disease brain is unaltered despite marked neuropathological changes.
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PMID:Calcium/calmodulin-dependent protein kinase II immunostaining is preserved in Alzheimer's disease hippocampal neurons. 782 Jun 30

The inhibition of voltage-activated Ca2+ channel currents by cortisol (hydrocortisone), the principal glucocorticoid in man and guinea pig, was examined in freshly dissociated pyramidal neurons from the adult guinea pig hippocampal CA1 region using whole-cell voltage-clamp recordings. Steady-state inhibition by cortisol of the peak Ca2+ channel current evoked by depolarization from -80 to -10 mV increased in a concentration-dependent fashion, with a maximal inhibition of 63 +/- 4% of the total current at 100 microM. Cortisone had a maximal 17 +/- 2% inhibition at 10 microM. Corticosterone and the metabolite allotetrahydrodeoxycorticosterone exhibited a plateau of inhibition of around 15% and 25%, respectively, between 10 pM and 100 nM; both compounds continued to inhibit at concentrations > 10(-7) M. Analysis of tail currents at -80 mV showed that cortisol and corticosterone had no effect on the voltage-dependent activation or deactivation of the Ca2+ channel current. However, cortisol slowed the activation of the current. Cortisol inhibited both the N-type or omega-conotoxin (CgTX)-sensitive, and the L-type or nifedipine (NIF)-sensitive Ca2+ channel current but had no effect on the CgTX/NIF-insensitive Ca2+ channel current. In neurons isolated from pertussis toxin (PTX)-treated animals, the cortisol inhibition was significantly diminished. Intracellular dialysis with GDP-beta-S (500 microM) or with the specific inhibitors of protein kinase C (PKC), the pseudosubstrate PKC inhibitor (PKCI 19-31) (2 microM) and bisindolylmaleimide (BIS) (1 microM) significantly diminished the cortisol inhibition of the Ca2+ channel current. The specific inhibitor of cAMP-dependent protein kinase (PKA) inhibitor, Rp-cAMPS (100 microM) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cortisol inhibition of calcium currents in guinea pig hippocampal CA1 neurons via G-protein-coupled activation of protein kinase C. 782 88

In the CA1 region of the hippocampus, activation of serotonin receptors of the 5-hydroxytryptamine (5-HT)4 subtype increases membrane excitability by reducing the calcium-activated potassium current responsible for the slow afterhyperpolarization observed in these cells. In the present study, the signaling mechanism by which 5-HT4 receptors reduce the afterhyperpolarization in the CA1 region was examined using intracellular recording in brain slices. Administration of the membrane-permeable cAMP analog 8-bromo-cAMP mimicked the effect of serotonin on the afterhyperpolarization, whereas administration of the protein kinase inhibitor staurosporine inhibited the effects of serotonin. These observations suggested a role for protein kinase A in this response. This was confirmed by intracellular injection of the selective protein kinase A inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate ((Rp)-cAMPS), which noncompetitively inhibited the ability of serotonin to reduce the after-hyperpolarization. Additional evidence for the involvement of cAMP in the signaling by 5-HT4 receptors was obtained using the general phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. When this compound was bath administered at concentrations sufficient to enhance a known cAMP-mediated response, a significant enhancement of the ability of 5-HT4 receptors to reduce the afterhyperpolarization was observed. Together, these results indicate that serotonin reduces the afterhyperpolarization in the CA1 region by acting on 5-HT4 receptors that increase intracellular cAMP levels and activate protein kinase A.
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PMID:Cyclic AMP and protein kinase A mediate 5-hydroxytryptamine type 4 receptor regulation of calcium-activated potassium current in adult hippocampal neurons. 783 28


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