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)

The complex circuitry of the CA3 region and the abundance of collateral connections has made it difficult to study the mossy fiber pathway in hippocampal slices and therefore to establish the site of expression of long-term potentiation at these synapses. Using a novel cell culture system, we have produced long-term potentiation of the elementary synaptic connections on single CA3 pyramidal neurons following tetanic stimulation of individual dentate gyrus granule cells. As is the case for the hippocampal slice, this potentiation was independent of N-methyl-D-aspartate receptor activation, was simulated by application of forskolin, and its induction did not require any modulatory input. The increase in synaptic strength was accompanied by a reduction in the number of failures of transmission and by an increase in the coefficient of variation of the responses and was prevented by presynaptic injection of an inhibitor of protein kinase A. These findings show that mossy fiber long-term potentiation has a presynaptic locus and that its expression is dependent on protein kinase A.
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PMID:A presynaptic locus for long-term potentiation of elementary synaptic transmission at mossy fiber synapses in culture. 864 68

cAMP and the cAMP-dependent protein kinase (PKA) are required in the mossy fiber pathway for both the early and the late phase of long-term potentiation (LTP). Since the CA3 region, which is the target of the mossy fibers, receives extensive noradrenergic innervation, we examined the role of beta-adrenergic receptors in mossy fiber LTP. We found that we could induce an early phase of LTP by pairing isoproterenol, a beta-adrenergic receptor agonist, with a weak train, subthreshold for LTP. This LTP was specific to the mossy fiber pathway, was blocked by inhibitors of PKA, and occluded paired-pulse facilitation, suggesting that isoproterenol was acting presynaptically. When isoproterenol was paired with a train that induced only the early phase of LTP, it gave rise to a protein synthesis-dependent late phase. Consistent with these findings, beta-adrenergic antagonists blocked both the late and the early phase of LTP induced by mossy fiber stimulation. Thus, beta-adrenergic receptor modulation is important for both phases of mossy fiber LTP.
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PMID:Modulation of both the early and the late phase of mossy fiber LTP by the activation of beta-adrenergic receptors. 878 58

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

Differences in calcium-mediated regulation of gap junctional intercellular communication (GJIC) between a cell line consisting of mouse epidermal initiated cells (3PC) and a mouse epidermal carcinoma-derived cell line (CA3/7) were studied. Under low extracellular calcium ((Ca2+)e) conditions (0.05 mM) CA3/7 cells showed a low level of GJIC compared with 3PC cells. High (Ca2+)e (1.20 mM) raised GJIC between CA3/7 cells to the GJIC level of 3PC cells, which in turn remained unchanged under these conditions. Raising the free intracellular calcium concentration ((Ca2+)i), using a calcium ionophore (ionomycin) or the Ca2+-ATPase inhibitor thapsigargin under low (Ca2+)e conditions, did not affect the GJIC level between 3PC cells, and increased GJIC between CA3/7 cells. Intracellular calcium chelation in 3PC cells under low (Ca2+)e conditions by ethylene glycol-bis(beta-amino-ethyl ether) N,N,N',N'-tetra-acetic acid acetoxy-methyl ester (EGTA-AM) decreased GJIC in this cell line. High (Ca2+)e conditions protected both cell lines from a decreased GJIC by EGTA-AM exposure. Inhibition of calmodulin (CaM) by calmidazolium (CDZ) or N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) under low (Ca2+)e conditions, inhibited GJIC in 3PC cells and increased GJIC in CA3/7 cells. Inhibition of Ca2+/CaM-dependent protein kinase (Ca2+/CaM-PK) by 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine (ML-7) decreased GJIC in both cell lines. Western analysis showed that Cx43 was more phosphorylated in both cell lines in concurrence with different effects on the GJIC level. Under conditions in which GJIC was inhibited, a decreased immunostaining of Cx43 on the plasma membrane was found. The level of immunostaining of the cell adhesion molecule E-cadherin on the plasma membranes of both cell types remained unchanged under conditions in which GJIC was changed by modulaters of (Ca2+)i, CaM activity, or the Ca2+/CaM-PK activity. These results indicate that differences exist between 3PC cells and CA3/7 cells in the GJIC regulation by intracellular calcium and calmodulin.
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PMID:Differences in the calcium-mediated regulation of gap junctional intercellular communication between a cell line consisting of initiated cells and a carcinoma-derived cell line. 896 43

The computational model was put forward of calcium-dependent posttetanic processes in the dendritic spine of CA3 hippocampal pyramidal neuron which received excitatory and inhibitory afferents. The system of differential equations enables description and evaluation of changes in protein kinase and protein phosphatase activity induced by changes in postsynaptic Ca2+ ion concentration (Cap2+). It was shown that the synaptic efficacy is determined by the ratio between active protein kinases and active protein phosphatase I. According to the proposed model, increase/decrease in Cap2+ concentration relative to the Cap2+ rise, produced by prior stimulation, results in the increase/decrease in the number of phosphorylated ionotropic receptors and in LTP/LTD synaptic efficacy. It follows form the model calculations that the same mechanisms underlie the LTP, LTD, and depotentiation. Some results of experimental study of the hippocampal and neocortical synaptic plasticity are explained and systematized.
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PMID:[The mathematical modelling of Ca2(+)-dependent postsynaptic processes in the hippocampus (the induction of long-term potentiation and long-term depression)]. 898 6

The modulation of high-threshold Ca current (I(Ca)) by adenosine receptors was studied using the voltage clamp method on acutely dissociated guinea pig hippocampal CA3 pyramidal neurons. When these neurons were exposed to adenosine in the presence of A1, A2a and A2b receptor antagonists, I(Ca) potentiation occurred at test potentials of -10 mV, but not at -40 mV. Similar potentiation also occurred using the A3 agonist N6-2-(4-aminophenyl)ethyl-adenosine (APNEA), either alone or in the presence of A1 and A2 antagonists. The putative A4 agonist 2-phenylaminoadenosine (CV-1808; Cornfield et al., 1992) did not potentiate I(Ca) at four concentrations tested between 25 nM and 2500 nM. K0.5 for the APNEA-induced potentiation was 25.4 nM, comparable to that determined in binding studies for the cloned receptor (15.5 nM; Zhou et al., 1992). I(Ca) potentiation by APNEA was blocked by intracellular application of WIPTIDE, a PKA inhibitor (p < 0.001), but was not affected by protein kinase C (PKC) inhibitor peptide (19-36). These results indicate that: (1) A3 receptor activation can significantly potentiate I(Ca), and (2) because the A3 receptor has been linked to down-regulation of adenylyl cyclase (Zhou et al., 1992), PKA appears to be negatively coupled to I(Ca).
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PMID:Adenosine A3 receptors potentiate hippocampal calcium current by a PKA-dependent/PKC-independent pathway. 917 14

Alterations of [3H]cyclic AMP (cAMP) binding, an indicator of the binding activity of particulate cyclic AMP-dependent protein kinase (PKA), were examined after 15 and 30 min of ischemia in the gerbil brain. Severe hemispheric cerebral ischemia was induced by occluding the right common carotid artery. Significant reductions in cAMP binding were noted only in the dendritic subfields of the hippocampus CA1 such as the strata oriens, radiatum and lacunosum-moleculare, on the ischemic side after 15 min of ischemia. After 30 min ischemia cAMP binding was significantly decreased not only in each dendritic subfield of the hippocampus CA1, but also in the layer of pyramidal cell bodies (stratum pyramidale) on the occluded side; other brain regions such as the hippocampus CA3, dentate gyrus and cerebral cortices revealed no significant changes in cAMP binding. These findings suggest that derangement of PKA may begin in the dendritic subfields of the hippocampus CA1 after as little as 15 min of severe ischemia, and proceed centrally to the neuronal cell bodies of the hippocampus CA1.
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PMID:Acute ischemic vulnerability of PKA in the dendritic subfields of the hippocampus CA1. 926 2

Kinase suppressor of Ras (KSR) is an evolutionarily conserved component of Ras-dependent signaling pathways. Here, we find that murine KSR (mKSR1) translocates from the cytoplasm to the plasma membrane in the presence of activated Ras. At the membrane, mKSR1 modulates Ras signaling by enhancing Raf-1 activity in a kinase-independent manner. The activation of Raf-1 is mediated by the mKSR1 cysteine-rich CA3 domain and involves a detergent labile cofactor that is not ceramide. These findings reveal another point of regulation for Ras-mediated signal transduction and further define a noncatalytic role for mKSR1 in the multistep process of Raf-1 activation.
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PMID:KSR stimulates Raf-1 activity in a kinase-independent manner. 937 54

In mossy fiber synapses of the CA3 region of the hippocampus, long-term potentiation (LTP) is induced presynaptically by activation of cAMP-dependent protein kinase A (PKA). Rab3A is a synaptic vesicle protein that regulates vesicle fusion and is essential for mossy fiber LTP. Rab3A probably acts via two effector proteins, rabphilin and RIM, of which rabphilin is an in vitro substrate for PKA. To test if rabphilin is phosphorylated in nerve terminals and if its PKA-dependent phosphorylation correlates with the PKA-dependent induction of LTP in mossy fiber terminals, we have studied the phosphorylation of rabphilin in synaptosomes isolated from the CA1 and CA3 regions of the hippocampus. Rabphilin was phosphorylated in both CA1 and CA3 synaptosomes. However, when we treated the CA1 and CA3 synaptosomes with forskolin (an agent that enhances PKA activity) or induced Ca2+ influx into synaptosomes with high K+, rabphilin phosphorylation was increased selectively in mossy fiber CA3 synaptosomes, but not in CA1 synaptosomes. In contrast, the phosphorylation of synapsin, studied as a control for the specificity of the region-specific phosphorylation of rabphilin, was augmented similarly by both treatments in CA1 and CA3 synaptosomes. These results reveal that the phosphorylation states of two synaptic substrates for PKA and CaM KII, rabphilin and synapsin, are regulated differentially in a region-specific manner, an unexpected finding because rabphilin and synapsin are similarly present in CA1 and CA3 synaptosomes and are colocalized on the same synaptic vesicles. The region-specific phosphorylation of rabphilin agrees well with the restricted induction of LTP by presynaptic PKA activation in mossy fiber, but not CA1, nerve terminals.
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PMID:Region-specific phosphorylation of rabphilin in mossy fiber nerve terminals of the hippocampus. 942 5


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