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)

Ca2+ influx through N-methyl-D-aspartate- (NMDA-) type glutamate receptors plays a critical role in synaptic plasticity in the brain. One of the proteins activated by the increase in Ca2+ is CaM kinase II (CaMKII). Here, we report a novel synaptic Ras-GTPase activating protein (p135 SynGAP) that is a major component of the postsynaptic density, a complex of proteins associated with synaptic NMDA receptors. p135 SynGAP is almost exclusively localized at synapses in hippocampal neurons where it binds to and closely colocalizes with the scaffold protein PSD-95 and colocalizes with NMDA receptors. The Ras-GTPase activating activity of p135 SynGAP is inhibited by phosphorylation by CaMKII located in the PSD protein complex. Inhibition of p135 SynGAP by CaMKII will stop inactivation of GTP-bound Ras and thus could result in activation of the mitogen-activated protein (MAP) kinase pathway in hippocampal neurons upon activation of NMDA receptors.
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PMID:A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. 962 Jun 94

We have applied techniques from modern molecular biology and biochemistry to unravel the complex molecular structure of the postsynaptic membrane at glutamatergic synapses in the central nervous system. We have characterized a set of new proteins that are constituents of the postsynaptic density, including PSD-95, densin-180, citron (a rho/rac effector protein), and synaptic gp130 Ras GAP (a new Ras GTPase-activating protein). The structure of PSD-95 revealed a new protein motif, the PDZ domain, that plays an important role in the assembly of signal transduction complexes at intercellular junctions. More recently, we have used new imaging tools to observe the dynamics of autophosphorylation of CaM kinase II in intact hippocampal tissue. We have been able to detect changes in the amount of autophosphorylated CaM kinase II in dendrites, individual synapses, and somas of hippocampal neurons following induction of long-term potentiation by tetanic stimulation. In addition, we have observed a specific increase in the concentration of CaM kinase II in dendrites of neurons receiving tetanic stimulation. This increase appears to be the result of dendritic synthesis of new protein. Over the next several years we will apply similar methods to study regulatory changes that occur at the molecular level in glutamatergic synapses in the CNS as the brain processes and stores new information.
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PMID:Signal transduction molecules at the glutamatergic postsynaptic membrane. 965 38

Synaptic NMDA-type glutamate receptors are anchored to the second of three PDZ (PSD-95/Discs large/ZO-1) domains in the postsynaptic density (PSD) protein PSD-95. Here, we report that citron, a protein target for the activated form of the small GTP-binding protein Rho, preferentially binds the third PDZ domain of PSD-95. In GABAergic neurons from the hippocampus, citron forms a complex with PSD-95 and is concentrated at the postsynaptic side of glutamatergic synapses. Citron is expressed only at low levels in glutamatergic neurons in the hippocampus and is not detectable at synapses onto these neurons. In contrast to citron, p135 SynGAP, an abundant synaptic Ras GTPase-activating protein that can bind to all three PDZ domains of PSD-95, and Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) are concentrated postsynaptically at glutamatergic synapses on glutamatergic neurons. CaM kinase II is not expressed and p135 SynGAP is expressed in less than half of hippocampal GABAergic neurons. Segregation of citron into inhibitory neurons does not occur in other brain regions. For example, citron is expressed at high levels in most thalamic neurons, which are primarily glutamatergic and contain CaM kinase II. In several other brain regions, citron is present in a subset of neurons that can be either GABAergic or glutamatergic and can sometimes express CaM kinase II. Thus, in the hippocampus, signal transduction complexes associated with postsynaptic NMDA receptors are different in glutamatergic and GABAergic neurons and are specialized in a way that is specific to the hippocampus.
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PMID:Citron binds to PSD-95 at glutamatergic synapses on inhibitory neurons in the hippocampus. 987 Sep 42

To elucidate the physiological significance of the translocation of Ca(2+)/calmodulin-dependent protein kinase II (CaM kinase II), we investigated substrates of CaM kinase II in the postsynaptic density (PSD). PSD proteins were phosphorylated by CaM kinase II of its PSD complex, and separated by two-dimensional gel electrophoresis. More than 28 proteins were phosphorylated under experimental conditions. Proteins corresponding to CaM kinase II substrates were excised from the gels, eluted electrophoretically, and then sequenced. Several substrates were identified, including PSD95, SAP90, alpha-internexin, neurofilament L chain, cAMP phosphodiesterase, and alpha- and beta-tubulin. Some substrates were also identified by immunoblotting, including N-methyl-D-aspartic acid (NMDA) receptor 2B subunit, 1-alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor 1 (GluR1), neurofilament H chain and dynamin. PSD95, SAP90, dynamin, and alpha-internexin were demonstrated for the first time to be substrates of CaM kinase II. NMDA receptor 2B subunit and GluR1 existed as major substrates in the PSD. Moreover, translocation of CaM kinase II was inhibited by phosphorylation of PSD proteins. These results suggest that CaM kinase II plays important roles in the regulation of synaptic functions through phosphorylation of PSD proteins.
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PMID:Investigation of protein substrates of Ca(2+)/calmodulin-dependent protein kinase II translocated to the postsynaptic density. 1100 Apr 84

Previous studies have suggested that the localization of the NMDA receptor NR1 subunit may be determined by the splice variant form of NR1 present. Functional studies have also supported selective targeting of NR2A and NR2B to synaptic and extrasynaptic populations, respectively. We set out to determine whether rat cortical and cerebellar NR1 splice variants and NR2 subunits are differentially localized to the postsynaptic density. Using western blot techniques, we measured the percentage of NR1 containing each cassette and the enrichment of the different cassettes and other proteins in the preparations. The results indicate that: (1) no single cassette of NR1 is differentially enriched in the postsynaptic densities and (2) the NR2A and NR2B subunits are similarly enriched at the synapse. The enrichment profiles of postsynaptic density-associated proteins demonstrated similar enrichment levels for postsynaptic density (PSD)-95, the NMDA receptor subunits, chapsyn-110, and the CaMKII alpha subunit. However, synaptophysin, SAP-102, and the GABA(A) receptor beta subunit exhibited lower enrichment levels compared to PSD-95. Additionally, cerebellar but not cortical PSDs exhibited significantly lower enrichment of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) GluR1. Thus, although postsynaptic densities are highly enriched in synaptic proteins, there appears to be no selective incorporation of specific NR1 splice variants or NR2 subunits into this structure.
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PMID:Enrichment of N-methyl-D-aspartate NR1 splice variants and synaptic proteins in rat postsynaptic densities. 1127 67

Activated T lymphoblasts respond more effectively to mitogenic stimuli than resting T cells, partly through differences in Ca(2+) signaling, which in turn depend on K(+) channel activity. Both Kv1.3 and Ca(2+)-activated K(+) (SK4) channels are up-regulated in T lymphoblasts. Since Ca(2+)- and calmodulin (CaM)-dependent signal-ing are key pathways in T-cell activation, we investigated their involvement in regulating the Kv1.3 current. Kv1.3 in lymphoblasts was significantly inhibited by elevating internal Ca(2+) to the micromolar level. It was also reduced in a Ca(2+)-dependent manner by inhibiting CaM with W-7 or calmidazolium. Part of the CaM-dependence is likely through CaM kinase since the current was also inhibited by the antagonist, KN-62, but not by the inactive analogue, KN-04. Kinase inhibition, unlike CaM inhibition, was only effective at physiological temperatures, a difference that implies involvement of more than one mechanism. We demonstrated a biochemical association of Kv1.3 protein in lymphoblasts with the multifunctional type II CaM kinase, but not with calmodulin. Thus, Kv1.3 forms a multi-protein complex with CaM kinase II (which binds to Ca(2+)/CaM) and previously identified proteins (e.g., PSD-95, src tyrosine kinase) that position the channel to respond to signaling pathways that are crucial for T-cell activation and proliferation.
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PMID:Regulation of Kv1.3 channels in activated human T lymphocytes by Ca(2+)-dependent pathways. 1141 Jul 8

Previously we detected more than 28 PSD proteins to be phosphorylated by CaM kinase II, and identified 14 protein substrates (Yoshimura, Y., Aoi, T., Yamauchi, T., Mol. Brain Res. 81, 118-128, 2000). In the present study, the remaining substrates were analyzed by protein sequencing and mass spectrometry. We found 6 proteins not previously known to be substrates of CaM kinase II, namely PSD95-associated protein, SAP97, TOAD-64, TNF receptor-associated protein, insulin-receptor tyrosine kinase 58/53 kDa substrate, and homer 1b.
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PMID:Identification of protein substrates of Ca(2+)/calmodulin-dependent protein kinase II in the postsynaptic density by protein sequencing and mass spectrometry. 1179 65

In contrast to the rapid regulation of AMPA receptors, previous evidence has supported the idea that the synaptic density of NMDA-type glutamate receptors is fairly static, modulated only over a long time scale in a homeostatic manner. We report here that selective activation of protein kinase C (PKC) with phorbol esters induces a rapid dispersal of NMDA receptors from synaptic to extrasynaptic plasma membrane in cultured rat hippocampal neurons. PKC activation induced a simultaneous translocation of calcium/calmodulin-dependent kinase II (CaMKII) to synapses but no change in spine number, presynaptic terminal number, or the distribution of AMPA receptors or the synaptic scaffolding protein PSD-95. PKC-induced accumulation of CaMKII was dependent on filamentous actin, whereas dispersal of NMDA receptors occurred by a different mechanism independent of actin or CaMKII. Consistent with the decrease in synaptic density of NMDA receptors, phorbol ester pretreatment reduced excitotoxicity. These results reveal a surprisingly dynamic nature to the molecular composition and functional properties of glutamatergic postsynaptic specializations.
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PMID:Rapid synaptic remodeling by protein kinase C: reciprocal translocation of NMDA receptors and calcium/calmodulin-dependent kinase II. 1189 55

CASK, an adaptor protein of the plasma membrane, is composed of an N-terminal calcium/calmodulin-dependent protein (CaM) kinase domain, central PSD-95, Dlg, and ZO-1/2 domain (PDZ) and Src homology 3 (SH3) domains, and a C-terminal guanylate kinase sequence. The CaM kinase domain of CASK binds to Mint 1, and the region between the CaM kinase and PDZ domains interacts with Velis, resulting in a tight tripartite complex. CASK, Velis, and Mint 1 are evolutionarily conserved in Caenorhabditis elegans, in which homologous genes (called lin-2, lin-7, and lin-10) are required for vulva development. We now demonstrate that the N-terminal CaM kinase domain of CASK binds to a novel brain-specific adaptor protein called Caskin 1. Caskin 1 and a closely related isoform, Caskin 2, are multidomain proteins containing six N-terminal ankyrin repeats, a single SH3 domain, and two sterile alpha motif domains followed by a long proline-rich sequence and a short conserved C-terminal domain. Unlike CASK and Mint 1, no Caskin homolog was detected in C. elegans. Immunoprecipitations showed that Caskin 1, like Mint 1, is stably bound to CASK in the brain. Affinity chromatography experiments demonstrated that Caskin 1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin 1, suggesting that CASK and Caskin 1 coat the cytoplasmic tails of neurexins and other cell-surface proteins. Detailed mapping studies revealed that Caskin 1 and Mint 1 bind to the same site on the N-terminal CaM kinase domain of CASK and compete with each other for CASK binding. Our data suggest that in the vertebrate brain, CASK and Velis form alternative tripartite complexes with either Mint 1 or Caskin 1 that may couple CASK to distinct downstream effectors.
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PMID:CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein. 1204 31

The PSD-95 protein family organizes the glutamatergic postsynaptic density and it is involved in the regulation of the excitatory signal at central nervous system synapses. We show here that PSD-95 deficiency by means of antisense oligonucleotides induces significant neuronal cell death within 24 h both in primary hippocampal cultures and in organotypic hippocampal slices. On the other hand, cultured cortical neurons are spared by PSD-95 antisense toxicity until they reach a NR2A detectable protein level (24 days in vitro). The neurotoxic event is characterized by increased alpha CaMKII association to NR2 regulatory subunits of NMDA receptor complex. As a direct consequence of alpha CaMKII association, we found increased GluR1 delivery to cell surface in cultured hippocampal neurons paralleled by AMPA-dependent increase in [Na+]I levels. In addition, both CaMKII specific inhibitor KN-93 and AMPA receptor antagonists CNQX and NBQX rescued neuronal survival to control values. On the other hand, both the NMDA channel blocker MK-801 and Dantrolene, an inhibitor of calcium release from ryanodine-sensitive endoplasmic reticulum stores, failed to have any effect on neuronal survival in PSD-95 deficient neurons. Thus, our data provide clues that PSD-95 reduced expression in neurons is responsible for neuronal vulnerability mediated by direct activation of alpha CaMKII transduction pathway in the postsynaptic compartment.
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PMID:Lack of PSD-95 drives hippocampal neuronal cell death through activation of an alpha CaMKII transduction pathway. 1237 13


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