Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.17 (CaMKII)
 4,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Both Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) and protein kinase C (PKC) have been implicated as possible candidates for contributing to the induction of long-term potentiation (LTP) in the hippocampus. The induction of LTP in the CA1 region of the hippocampus, an event which requires postsynaptic Ca2+ influx through NMDA-type glutamate receptors, is blocked by calmodulin antagonists and inhibitors of CaM kinase II and PKC. In the present study, we describe the activation characteristics of CaM kinase II and PKC through the stimulation of glutamate receptors and regulation of the phosphorylation of substrates for CaM kinase II in the hippocampus. In cultured rat hippocampal neurons, glutamate elevated the Ca(2+)-independent activity of CaM kinase II through autophosphorylation, and this response was blocked by specific antagonists of the NMDA receptor. In addition, glutamate stimulated the translocation of PKC from the cytosol to the membrane fraction through the metabotropic glutamate receptor. In the experiments with 32P-labeled cells, the phosphorylation of microtubule-associated protein 2 (MAP2) and synapsin I was stimulated by the exposure to glutamate. Finally, we demonstrated that high, but not low, frequency stimulation applied to two groups of CA1 afferents in the slices resulted in the induction of LTP with concomitant long-lasting increases in the Ca(2+)-independent and total CaM kinase II activities as well as the autophosphorylation. It could be blocked by preincubation of the slices with NMDA-receptor antagonist. These results suggest that glutamate can activate CaM kinase II through NMDA receptors in the induction of LTP and in turn stimulates the phosphorylation of target proteins such as MAP2 and synapsin I.
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PMID:[The role of Ca2+/calmodulin-dependent protein kinase II in the cellular signal transduction]. 828 67

The effects of cAMP-dependent protein kinase (cAMP-PK) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation on the calpain-mediated degradation of microtubule-associated protein 2 (MAP-2) were studied. Both cAMP-PK and CaMKII readily phosphorylated MAP-2. However, cAMP-PK phosphorylated MAP-2 to a significantly greater extent than did CaMKII (4.5 mol 32P/mol MAP-2 and 1.4 mol 32P/mol MAP-2, respectively). Phosphorylation of MAP-2 by cAMP-PK, but not by CaMKII, significantly inhibited the calpain-induced hydrolysis of MAP-2. These results demonstrate that the phosphorylation of sites on the MAP-2 molecule accessible to cAMP-PK, but not to CaMKII, result in increased resistance to calpain proteolysis.
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PMID:Calpain-mediated proteolysis of microtubule-associated protein 2 (MAP-2) is inhibited by phosphorylation by cAMP-dependent protein kinase, but not by Ca2+/calmodulin-dependent protein kinase II. 839 Oct 85

Many of the extracellular signals such as neurotransmitters and hormones regulate the intracellular concentration of second messengers such as cAMP, cGMP, and calcium ion (Ca2+), diacylglycerol and IP3. Accumulating evidence indicates that protein phosphorylation-dephosphorylation is an important mechanism by which second messengers act to regulate a variety of cellular processes. Ca2+/calmodulin-dependent protein kinase II, cAMP-dependent protein kinase and protein kinase C are three major classes of protein kinases in the central nervous system. In an attempt to elucidate the physiological roles of the protein kinases, I have been studying the substrate proteins and functional significance of the enzymes and phosphorylated proteins. For these purposes, I investigated the phosphorylation-dephosphorylation of cytoskeletal proteins such as microtubule-associated protein 2 and tau, which are involved in the assembly-disassembly of microtubules and the production of abnormally phosphorylated forms of tau in neurofibrillary tangles in Alzheimer's disease brain. As the natural consequence, studying the protein phosphatases is significant for elucidating the switch-off mechanism of protein phosphorylation. Thus, I have been investigating the functional significance of protein phosphorylation-dephosphorylation for the elucidation of signal transduction in the brain, which is widely involved in the regulation of brain functions.
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PMID:[Molecular and pharmacological studies on signal transduction in the brain]. 872 Feb 94

The observation that autophosphorylation converts CaM kinase II from the Ca(2+)-dependent form to the Ca(2+)-independent form has led to speculation that the formation of the Ca(2+)-independent form of the enzyme could encode frequency of synaptic usage and serve as a molecular explanation of "memory". In cultured rat hippocampal neurons, glutamate elevated the Ca(2+)-independent activity of CaM kinase II through autophosphorylation, and this response was blocked by an NMDA receptor antagonist, D-2-amino-5-phosphonopentanoate (AP5). In addition, we confirmed that high, but not low frequency stimulation, applied to two groups of CA1 afferents in the rat hippocampus, resulted in LTP induction with concomitant long-lasting increases in Ca(2+)-independent and total activities of CaM kinase II. In experiments with 32P-labeled hippocampal slices, the LTP induction in the CA1 region was associated with increases in autophosphorylation of both alpha and beta subunits of CaM kinase II 1 h after LTP induction. Significant increases in phosphorylation of endogenous CaM kinase II substrates, synapsin I and microtubule-associated protein 2 (MAP2), which are originally located in presynaptic and postsynaptic regions, respectively, were also observed in the same slice. All these changes were prevented when high frequency stimulation was applied in the presence of AP5 or a calmodulin antagonist, calmidazolium. Furthermore, in vitro phosphorylation of the AMPA receptor by CaM kinase II was reported in the postsynaptic density and infusion of the constitutively active CaM kinase II into the hippocampal neurons enhanced kainate-induced response. These results support the idea that CaM kinase II contributes to the induction of hippocampal LTP in both postsynaptic and presynaptic regions through phosphorylation of target proteins such as the AMPA receptor, MAP2 and synapsin I.
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PMID:CaM kinase II in long-term potentiation. 874 Apr 40

A small number of mRNAs, including Ca2+/calmodulin-dependent protein kinase II alpha-subunit (CamKIIalpha) mRNA and microtubule-associated protein 2 (MAP2) mRNA, are present in the dendrites of neurones as well as in the cell bodies. We show here that the induction of long-term potentiation (LTP) in the hippocampal perforant path/granule cell synapses in anaesthetised rats is associated with increased levels of CamKIIalpha mRNA and MAP2 mRNA in the granule cell dendrites after 2 h. Similarly, induction of LTP in the Schaffer collateral/CA1 pyramidal cell synapses in hippocampal slices maintained in vitro also results in elevated dendritic levels of CamKIIalpha mRNA and MAP2 mRNA 2 h later. In both models, the levels of various other mRNA species restricted to the cell body region were unaffected by the induction of LTP. Increased expression of dendritic CamKIIalpha mRNA and MAP2 mRNA appears to be a general feature of hippocampal plasticity, since it occurs following LTP induction in both the dentate gyrus and the CA1 region. The elevation of mRNA levels in a restricted region close to the afferent synapses would allow a highly-localised enhancement of the synthesis of the corresponding proteins, providing an elegant mechanism for protein-synthesis-dependent synaptic plasticity to maintain a high degree of anatomical specificity.
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PMID:Increased expression of dendritic mRNA following the induction of long-term potentiation. 960 46

Several lines of evidence suggest that the mechanism of action of antidepressant drugs (AD) involves adaptive changes occurring in intraneuronal post-receptor signal transduction cascades. Protein phosphorylation has a key role in signal transduction and was previously found to be a target in the action of AD (5-HT and/or NA reuptake blockers). Several studies showed that cAMP- and type II Ca2+/calmodulin-dependent protein kinases (PKA and CaMKII) are markedly affected by typical AD in two different and complementary cellular districts, respectively microtubules (a somatodendritic compartment) and synaptic vesicles (a presynaptic terminal compartment). In order to investigate whether the effect on protein kinases may be involved in the therapeutic action of drugs it is interesting to compare the effect of atypical AD with that of typical drugs. In this study the effect of the atypical AD S-adenosylmethionine (SAMe) was tested. Repeated (12 days) SAMe treatment induced in cerebrocortical microtubules an increase in the binding of cAMP to the RII PKA regulatory subunit and an increase in the endogenous phosphorylation of microtubule-associated protein 2, an effect resembling that of typical AD. In synaptic terminals the treatment induced an increase in the activity of CaMKII and in the endogenous phosphorylation of vesicular substrates. However, this modification was found in the cerebral cortex rather than in the hippocampus, where typical AD affect CaMKII. In addition the synapsin I level was decreased in the hippocampus and increased in the cerebral cortex, an effect not detected with typical AD.
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PMID:Modifications in brain cAMP- and calcium/calmodulin-dependent protein kinases induced by treatment with S-adenosylmethionine. 983 37

Previous studies showed that the type II Ca(2+)/calmodulin- and cAMP-dependent protein kinases (CaMKII and PKA) are affected by long-term antidepressant treatment in presynaptic and somatodendritic compartments, respectively. This study describes the long-term effects of the selective noradrenaline reuptake inhibitor reboxetine on PKA and CaMKII, in both the microtubule and subsynaptosomal fractions of rat brain. Unlike other antidepressants, chronic reboxetine induced in the cerebrocortical soluble and microtubule fractions a decrease in the [(32)P]cAMP binding to the type II PKA regulatory subunit. No change in the cAMP-dependent endogenous phosphorylation of the protein substrate, microtubule-associated protein 2 was observed. In the hippocampal subsynaptosomal fractions (synaptic vesicles and synaptosomal membranes) reboxetine induced a robust increase in the activity but not in the expression of CaMKII. An increase in the calcium/calmodulin-dependent phosphorylation of presynaptic substrates was also detected. These findings showed that reboxetine modulates post-receptor signal transduction systems in rat brain.
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PMID:Effect of reboxetine treatment on brain cAMP- and calcium/calmodulin-dependent protein kinases. 1116 38

In neurons, translation of dendritically localized mRNAs is thought to play a role in affecting synaptic efficacy. Inasmuch as components of the translation machinery may be limiting in dendrites, we investigated the mechanisms by which translation of five dendritically localized mRNAs is initiated. The 5' leader sequences of mRNAs encoding the activity-regulated cytoskeletal protein, the alpha subunit of calcium-calmodulin-dependent kinase II, dendrin, the microtubule-associated protein 2, and neurogranin (RC3) were evaluated for their ability to affect translation in the 5' untranslated region of a monocistronic reporter mRNA. In both neural and nonneural cell lines, the activity-regulated cytoskeletal protein, microtubule-associated protein 2, and alpha-CaM Kinase II leader sequences enhanced translation, whereas the dendrin and RC3 5' untranslated regions slightly inhibited translation as compared with controls. When cap-dependent translation of these constructs was suppressed by overexpression of a protein that binds the cap-binding protein eIF4E, it was revealed that translation of these mRNAs had both cap-dependent and cap-independent components. The cap-independent component was further analyzed by inserting the 5' leader sequences into the intercistronic region of dicistronic mRNAs. All five leader sequences mediated internal initiation via internal ribosome entry sites (IRESes). The RC3 IRES was most active and was further characterized after transfection in primary neurons. Although translation mediated by this IRES occurred throughout the cell, it was relatively more efficient in dendrites. These data suggest that IRESes may increase translation efficiency at postsynaptic sites after synaptic activation.
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PMID:Internal initiation of translation of five dendritically localized neuronal mRNAs. 1122 15

In mammalian neurons a selected group of mRNAs, including the transcript encoding the alpha subunit of Ca2+/calmodulin-dependent protein kinase II, is found in dendrites. The molecular mechanisms underlying extrasomatic RNA trafficking are not well described. It is thought that dendritic transcripts contain cis-acting elements that direct their selective subcellular sorting. Here we report the identification of an extrasomatic targeting element in the 3' untranslated region of the mRNA encoding the alpha subunit of Ca2+/calmodulin-dependent protein kinase II. In primary hippocampal neurons, this 1200-nucleotide-spanning, cis-acting element is sufficient to mediate dendritic localization of chimeric reporter transcripts. The trafficking signal does not share any striking sequence similarity with a previously characterized dendritic targeting element in transcripts encoding the microtubule-associated protein 2. In dendrites of transfected primary neurons, recombinant RNAs form granules with an average diameter of 0.45 microm that may represent preferential RNA docking sites or multimolecular transport units. These findings imply that extrasomatic sorting of individual dendritic mRNAs involves at least partially distinct molecular mechanisms, as well as large trafficking complexes.
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PMID:Identification of a cis-acting dendritic targeting element in the mRNA encoding the alpha subunit of Ca2+/calmodulin-dependent protein kinase II. 1140 81


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