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)

The formation of spinules at the terminal dendrites of retinal horizontal cells with the onset of light and their subsequent retraction during darkness is a remarkable example of synaptic plasticity where sensory experience modifies reversibly, and on a time scale of minutes the ultrastructure of synaptic connectivity. The signals and the subsequent intracellular cascades underlying the prominent morphological alterations are only partially understood. We show here that lowering the external calcium concentration did prevent dark- and AMPA-induced retraction of spinules in a eyecup preparation. Furthermore, spinule retraction was prevented in vivo by the injection of calmidazolium, an inhibitor of calmodulin, into the eyeball, and also by the injection of KN-62, an inhibitor of Ca2+/calmodulin-dependent protein kinase (CaMkII). We conclude that local Ca2+ influx through AMPA-gated channels followed by activation of CaMkII is an important step for spinule retraction during dark adaptation. The phosphorylation patterns of phosphoproteins derived from purified horizontal cells was affected by the inhibitors of calmodulin and CaMkII respectively. Some of the affected phosphoproteins appeared to be cytoskeleton-associated proteins, including GAP-43. Based on these observations, a putative scenario for the retraction of spinules is proposed.
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PMID:Retraction of spinule-type neurites from carp retinal horizontal cell dendrites during dark adaptation involves the activation of Ca2+/calmodulin-dependent protein kinase II. 852 66

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

Brain synaptic junctions are marked by a prominent dense-staining structure, the postsynaptic density (PSD), embedded in the postsynaptic membrane. Isolated PSDs contain a complex mixture of proteins among which the most abundant are the alpha subunit of calcium/calmodulin-dependent kinase II (CaMK II alpha) the membrane cytoskeletal proteins actin and spectrin and receptors for both excitatory and inhibitory neurotransmitters. We have investigated the relationship of these proteins to the junctional structure by extracting isolated PSDs with lithium diiodosalicylate (LIS). This selectively solubilized actin and spectrin while other prominent PSD proteins, such as CaMK II alpha, the AMPA- and NMDA-type glutamate receptors and GABA receptors, were not extracted at all. Electron microscopy revealed that LIS treatment caused some fragmentation of PSDs but that their basic lattice-like structure remained intact. These observations suggest that PSD structure is organised at two levels; a core component containing CaMK II alpha and neurotransmitter receptors which we have previously described as the postsynaptic junctional lattice and a peripheral actin-associated component that draws the lattice components together into the complete PSD structure.
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PMID:Role of actin in the organisation of brain postsynaptic densities. 903 39

To study potential molecular mechanisms of epileptogenesis in the neocortex, the motor cortex of rats was injected with tetanus toxin (TT), and gene expression for 67 kDa glutamic acid decarboxylase (GAD-67), type II calcium/calmodulin-dependent protein kinase (CaMKII), NMDA receptor subunit 1 (NR1), and AMPA receptor subunit 2 (GluR2) was investigated by in situ hybridization histochemistry. Injections of 20-35 ng TT induced recurrent seizures after a postoperative period ranging from 4 to 13 d. A majority of rats perfused 5-7 d after TT injection showed altered gene expression, but the changes varied in their areal extent, ranging from most neocortical areas on the injected side in some rats to mainly the frontoparietal cortex or the motor cortex in others. Epileptic rats perfused 14 d after TT injection showed a focus of increased GAD-67 and NR1, and of decreased alpha-CaMKII and GluR2 mRNA levels at the injection site. A zone of cortex surrounding the focus showed changes in alpha-CaMKII, GAD-67, and NR1 mRNA levels that were reciprocal to those in the focus. The results suggest that TT-induced seizure activity initially spread to a variable extent but was gradually restricted 2-3 d after seizure onset. The focus and the surround showing reciprocal changes in gene expression are thought to correspond to the electrophysiologically identified epileptic focus and inhibitory surround, respectively. The findings suggest that lateral inhibition between neighboring cortical regions will be affected and contribute to a neurochemical segregation of an epileptic focus from surrounding cortex.
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PMID:Differential and time-dependent changes in gene expression for type II calcium/calmodulin-dependent protein kinase, 67 kDa glutamic acid decarboxylase, and glutamate receptor subunits in tetanus toxin-induced focal epilepsy. 904 41

We have detected immunoreactivities of AMPA receptor subunits GluR1-4 in post-synaptic density (PSD) fraction and tested whether they can be phosphorylated by endogenous kinases. Incubation of PSD with Ca2+ and calmodulin increased phosphorylation of GluR1 and GluR2/3. The phosphorylation of GluR1 was largely blocked by a Ca2+/calmodulin-dependent protein kinase type II inhibitor. Thus Ca2+/calmodulin-dependent phosphorylation of glutamate receptor may be a mechanism underlying enhanced post-synaptic receptor responsiveness in LTP.
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PMID:Calcium- and calmodulin-dependent phosphorylation of AMPA type glutamate receptor subunits by endogenous protein kinases in the post-synaptic density. 919 Nov 13

Aberrant phosphorylation of neurofilaments, similar to that occurring in various motor neuron diseases, is produced in cultured motor neurons by activation of protein kinase C (PKC). Following exposure to synthetic diacylglycerol, persistent change in the phosphorylation state of C-terminal domains of neurofilament proteins was detected by increased perikaryal immunoreactivity with the antibody SMI34; this antibody recognizes NF-M/NF-H when C-terminal KSP repeat domains are highly phosphorylated. SMI34 labeling of perikarya and dendrites was prevented by pretreatment with either the NMDA receptor antagonist APV or by the Ca2+/calmodulin-dependent protein kinase (CaMK) inhibitor KN-62, but not by antagonists of AMPA/kainate or metabotropic glutamate receptors or by inhibitors of arachidonic acid metabolic pathways. Thus, activation of PKC may induce neurofilament phosphorylation in motor neurons by acting in cooperation with stimulation of NMDA receptors and activation of CaMK. These mechanisms may be relevant to motor neuron disease and other neuronal injuries in which increased PKC activity has been measured.
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PMID:Activation of NMDA receptors and Ca2+/calmodulin-dependent protein kinase participate in phosphorylation of neurofilaments induced by protein kinase C. 940 13

GluR2 is the regulatory subunit in the AMPA family of glutamate receptors (GluRs) in that its presence inhibits calcium flux and dominates the current/ voltage characteristics of AMPA receptors. Studies from other laboratories have shown that GABAergic interneurons have a lower ratio of GluR2/GluR1 mRNA than pyramidal cells as well as possessing AMPA receptors that have a higher relative permeability to calcium. We hypothesized that such differences might be related to differences in the subunit stoichiometry at the AMPA synapses in each cell class, and used a GluR2-specific monoclonal antibody in a double-label immunogold protocol with anti-GABA and anti-CaM kinase II to compare the GluR2 representation at asymmetric synapses in GABA neurons to that of pyramidal cells in rat CA1. Virtually all CA1 pyramidal cells as well as the majority of GABAergic interneurons were GluR2 positive. EM immunogold labeling also showed that GABAergic interneurons had distinctive ultrastructural features and contained GluR2 in both their soma and their dendrites, as did the spines and shafts of pyramidal cells. GluR2 immunoreactivity was frequently preferentially located at asymmetric synapses on both pyramidal cell spines and shafts as well as the dendritic processes and soma of GABAergic interneurons. However, the labeled synapses on GABAergic neurons had a significantly lower number of immunogold particles than those on pyramidal cells. In fact, 90% of the labeled asymmetric synapses on GABAergic cells had one to three gold particles, whereas greater than 70% of the labeled asymmetric synapses on pyramidal cells had four or more gold particles associated with the synapse. These data suggest that while both cell classes contain GluR2, they differ in the relative representation of GluR2 at their AMPA synapses, such that GABAergic neurons might possess AMPA receptors with higher calcium permeability on average than pyramidal cells. Such differences in subunit representation at AMPA-receptor-mediated synapses would not only lead to differences in calcium permeability and functional characteristics across these two cell classes, but might also be relevant to the hippocampal patterns of selective vulnerability with respect to excitotoxicity and neurodegeneration.
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PMID:Synaptic distribution of GluR2 in hippocampal GABAergic interneurons and pyramidal cells: a double-label immunogold analysis. 951 19

The studies discussed in this review demonstrate that phosphorylation is an important mechanism for the regulation of ligand-gated ion channels. Structurally, ligand-gated ion channels are heteromeric proteins comprised of homologous subunits. For both the AChR and the GABA(A) receptor, each subunit has a large extracellular N-terminal domain, four transmembrane domains, a large intracellular loop between transmembrane domains M3 and M4, and an extracellular C-terminal domain (Fig. 1B). All the phosphorylation sites on these receptors have been mapped to the major intracellular loop between M3 and M4 (Table 1). In contrast, glutamate receptors appear to have a very large extracellular N-terminal domain, one membrane hairpin loop, three transmembrane domains, a large extracellular loop between transmembrane domains M3 and M4, and an intracellular C-terminal domain (Fig. 1C). Most phosphorylation sites on glutamate receptors have been shown to be on the intracellular C-terminal domain, although some have been suggested to be on the putative extracellular loop between M3 and M4 (Table 1). A variety of extracellular factors and intracellular signal transduction cascades are involved in regulating phosphorylation of these ligand-gated ion channels (Fig. 2). Once again, the AChR at the neuromuscular junction is the most fully understood system. Phosphorylation of the AChR by PKA is stimulated synaptically by the neuropeptide CGRP and in an autocrine fashion by adenosine released from the muscle in response to acetylcholine. In addition, acetylcholine, via calcium influx through the AChR, appears to activate calcium-dependent kinases including PKC to stimulate serine phosphorylation of the receptor. Presently, agrin is the only extracellular factor known to stimulate phosphorylation of the AChR on tyrosine residues. For glutamate receptors, non-NMDA receptor phosphorylation by PKA is stimulated by dopamine, while NMDA receptor phosphorylation by PKA and PKC can be induced via the activation of beta-adrenergic receptors, and metabotropic glutamate or opioid receptors, respectively. In addition, Ca2+ influx through the NMDA receptor has been shown to activate PKC. CaMKII, and calcineurin, resulting in phosphorylation of AMPA receptors (by CaMKII) and inactivation of NMDA receptors (at least in part through calcineurin). In contrast to the AChR and glutamate receptors, no information is presently available regarding the identities of the extracellular factors and intracellular signal transduction cascades that regulate phosphorylation of the GABA(A) receptor. Surely, future studies will be aimed at further clarifying the molecular mechanisms by which the central receptors are regulated. The presently understood functional effects of ligand-gated ion channel phosphorylation are diverse. At the neuromuscular junction, a regulation of the AChR desensitization rate by both serine and tyrosine phosphorylation has been demonstrated. In addition, tyrosine phosphorylation of the AChR or other synaptic components appears to play a role in AChR clustering during synaptogenesis. For the GABA(A) receptor, the data are complex. Both activation and inhibition of GABA(A) receptor currents as a result of PKA and PKC phosphorylation have been reported, while phosphorylation by PTK enhances function. The predominant effect of glutamate receptor phosphorylation by a variety of kinases is a potentiation of the peak current response. However, PKC also modulates clustering of NMDA receptors. This complexity in the regulation of ligand-gated ion channels by phosphorylation provides diverse mechanisms for mediating synaptic plasticity. In fact, accumulating evidence supports the involvement of protein phosphorylation and dephosphorylation of AMPA receptors in LTP and LTD respectively. There has been a dramatic increase in our understanding of the nature by which phosphorylation regulates ligand-gated ion channels. However, many questions remain unanswered. (AB
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PMID:Regulation of ligand-gated ion channels by protein phosphorylation. 1021 14

Recent studies have suggested that protein phosphorylation of glutamate receptors may play an important role in synaptic transmission. Specifically, the phosphorylation of AMPA receptors has been implicated in cellular models of synaptic plasticity. The phosphorylation of the glutamate receptor 1 (GluR1) subunit of AMPA receptors by protein kinase A (PKA), protein kinase C (PKC), and Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been characterized extensively. Phosphorylation of this subunit occurs exclusively on the intracellular C-terminal domain. However, the GluR1 subunit C terminus shows low homology to the other AMPA receptor subunits. In this paper we characterized the phosphorylation of AMPA receptor subunit GluR4, using site-specific mutagenesis and biochemical techniques. We found that GluR4 is phosphorylated on serine 842 within the C-terminal domain in vitro and in vivo. Serine 842 is phosphorylated by PKA, PKC, and CaMKII in vitro and is phosphorylated in transfected cells by PKA. Two-dimensional phosphopeptide analysis indicates that serine 842 is the major phosphorylation site on GluR4. In addition, we identified threonine 830 as a potential PKC phosphorylation site. These results suggest that GluR4, which is the most rapidly desensitizing AMPA receptor subunit, may be modulated by phosphorylation.
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PMID:Characterization of phosphorylation sites on the glutamate receptor 4 subunit of the AMPA receptors. 1036 8

Ca(2+)-permeable AMPA receptors may play a key role during developmental neuroplasticity, learning and memory, and neuronal loss in a number of neuropathologies. However, the intracellular signaling pathways used by AMPA receptors during such processes are not fully understood. The mitogen-activated protein kinase (MAPK) cascade is an attractive target because it has been shown to be involved in gene expression, synaptic plasticity, and neuronal stress. Using primary cultures of mouse striatal neurons and a phosphospecific MAPK antibody we addressed whether AMPA receptors can activate the MAPK cascade. We found that in the presence of cyclothiazide, AMPA caused a robust and direct (no involvement of NMDA receptors or L-type voltage-sensitive Ca(2+) channels) Ca(2+)-dependent activation of MAPK through MAPK kinase (MEK). This activation was blocked by GYKI 53655, a noncompetitive selective antagonist of AMPA receptors. Probing the mechanism of this activation revealed an essential role for phosphatidylinositol 3-kinase (PI 3-kinase) and the involvement of a pertussis toxin (PTX)-sensitive G-protein, a Src family protein tyrosine kinase, and Ca(2+)/calmodulin-dependent kinase II. Similarly, kainate activated MAPK in a PI 3-kinase-dependent manner. AMPA receptor-evoked neuronal death and arachidonic acid mobilization did not appear to involve signaling through the MAPK pathway. However, AMPA receptor stimulation led to a Ca(2+)-dependent phosphorylation of the nuclear transcription factor CREB, which could be prevented by inhibitors of MEK or PI 3-kinase. Our results indicate that Ca(2+)-permeable AMPA receptors transduce signals from the cell surface to the nucleus of neurons through a PI 3-kinase-dependent activation of MAPK. This novel pathway may play a pivotal role in regulating synaptic plasticity in the striatum.
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PMID:Ca(2+)-permeable AMPA receptors induce phosphorylation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signaling cascade in neurons. 1040 26


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