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)

GluR1 and GluR2 subunits compose AMPA receptors (AMPARs) in the mature hippocampus, and both the GluR1 subunit and Ca2+/calmodulin-dependent protein kinase II (CaMKII) are required for synaptic plasticity, memory and learning. Although GluR1 phosphorylationby CaMKII is preserved, the functional regulation of AMPARs by phosphorylation is lost in the presence of the GIuR2 subunit. Our findings define a previously unknown, dominant role of the GluR2 subunit in signaling mediated by CaMKII at AMPARs.
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PMID:Dominant role of the GluR2 subunit in regulation of AMPA receptors by CaMKII. 1592 37

A widely studied example of vertebrate plasticity is LTP (long-term potentiation), the persistent synaptic enhancement that follows a brief period of coinciding pre- and post-synaptic activity. During LTP, different kinases, including CaMKII (calcium/calmodulin-dependent protein kinase II) and protein kinase A, become activated and play critical roles in induction and maintenance of enhanced transmission. Biochemical analyses have revealed several regulated phosphorylation sites in the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor subunits, GluR1 and GluR4. The regulated insertion of these receptors is a key event in the induction of LTP. Here, we discuss the phosphorylation of GluR1 and GluR4 and its role in receptor delivery and neuronal plasticity.
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PMID:AMPA receptor phosphorylation during synaptic plasticity. 1624 17

Ca2+ influx through the NMDA receptor and subsequent activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) are crucial for learning and one of its physiological correlates, long-term potentiation (LTP). Ca2+/calmodulin promotes CaMKII binding to several postsynaptic proteins, including the NMDA receptor. These interactions strategically place CaMKII at locations where Ca2+ influx through the NMDA receptor is highest for further activation of CaMKII and for phosphorylation of nearby AMPA receptors and of other proteins that are important for LTP. Ca2+-dependent postsynaptic CaMKII clustering is of specific interest because LTP is synapse specific: only synapses that experience LTP-inducing high-frequency activity exhibit LTP. Ca2+-driven protein binding ensures that CaMKII accumulates only at those synapses undergoing LTP. This selectivity is economical and could contribute to the synapse specificity of LTP because downstream effects of CaMKII will occur mainly at synapses that accumulate CaMKII. In this article, we provide an overview of recent progress in postsynaptic CaMKII anchoring and discuss its implication in synaptic plasticity and the etiology and potential treatments of neurological diseases.
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PMID:Activity-driven postsynaptic translocation of CaMKII. 1625 51

The phytoplankton-derived neurotoxin, domoic acid (DOM), frequently causes poisoning of marine animals and poses an increasing threat to public health through contamination of seafood. In this study, we used stereotactic microinjection technique to administer varying amounts of DOM into the hippocampal CA1 region in order to examine potential histopathological changes after injection of sub-lethal concentrations to CA1 pyramidal neurons. Gross anatomical abnormalities in CA1 were observed at above 10 microM DOM (3 pmol in 0.3 microl saline). At 1mM concentration, DOM produces both ipsilateral and contralateral neuronal cell death in CA1, CA3 as well as dentate gyrus subfields. Animal behavioral changes after microinjection were similar to those observed by previous studies through systemic DOM injection. Neuronal degeneration was paralleled by reduced glutamate receptor (NR1, GluR1 and GluR6/7) immunolabeling throughout the whole hippocampal formation. Pre-injection of the AMPA/KA receptor antagonist NBQX (10 microM, 0.3 microl) blocked 1mM DOM-induced neuronal degeneration as well as behavioral symptoms. At concentrations lower than 10 microM, no histopathological changes were observed microscopically, nor were the levels of immunostaining of NR1, GluR1, GluR6/7 different. However, increased immunolabeling of autophosphorylated calcium-calmodulin-dependent kinase II (CaMKII, p-Thr286) and phosphorylated cAMP response element binding protein (CREB, p-Ser133) were observed at 24 h post-injection, suggesting that altered intracellular signal transduction mediated by GluRs might be an adaptive cellular protective mechanism against DOM-induced neurotoxicity.
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PMID:Histopathological and molecular changes produced by hippocampal microinjection of domoic acid. 1652 7

A prominent cognitive impairment after traumatic brain injury (TBI) is hippocampal-dependent memory loss. Although the histopathologic changes in the brain are well documented after TBI, the underlying biochemical mechanisms that contribute to memory loss have yet to be thoroughly delineated. Thus, we determined if calcium/calmodulin-dependent protein kinases (CaMKs), known to be necessary for the formation of hippocampal-dependent memories, are regulated after TBI. Sprague-Dawley rats underwent moderate parasagittal fluid-percussion brain injury on the right side of the parietal cortex. The ipsilateral hippocampus and parietal cortex were Western blotted for phosphorylated, activated alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMKII), CaMKIV, and CaMKI. alpha-Calcium/calmodulin-dependent protein kinase II was activated in membrane subcellular fractions from the hippocampus and parietal cortex 30 mins after TBI. CaMKI and CaMKIV were activated in a more delayed manner, increasing in phosphorylation 1 h after TBI. The increase in activated alpha-CaMKII in membrane fractions was accompanied by a decrease in cytosolic total alpha-CaMKII, suggesting redistribution to the membrane. Using confocal microscopy, we observed that alpha-CaMKII was activated within hippocampal neurons of the dentate gyrus, CA3, and CA1 regions. Two downstream substrates of alpha-CaMKII, the AMPA-type glutamate receptor GluR1, and cytoplasmic polyadenylation element-binding protein, concomitantly increased in phosphorylation in the hippocampus and cortex 1 h after TBI. These results demonstrate that several of the biochemical cascades that subserve memory formation are activated unselectively in neurons after TBI. As memory formation requires activation of CaMKII signaling pathways at specific neuronal synapses, unselective activation of CaMKII signaling in all synapses may disrupt the machinery for memory formation, resulting in memory loss after TBI.
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PMID:Activation of calcium/calmodulin-dependent protein kinases after traumatic brain injury. 1657 77

It has been suggested that antagonists at serotonin 5-HT1A receptors may exert a procognitive effect by facilitating glutamatergic neurotransmission. Here we further explored this issue by looking for the ability of a 5-HT1A antagonist to prevent the learning deficit induced by AMPA receptor blockade in two behavioural procedures in rats, and for concomitant molecular changes presumably involved in memory formation in the hippocampus. Pretraining administration of the competitive AMPA receptor antagonist, NBQX, produced a dose-related retention impairment in a passive avoidance task 24h later, and also impaired retention in a novel object recognition test when an intertrial interval of 3h was selected. Pretreatment with the selective 5-HT1A receptor antagonist, WAY-100635, prevented the learning deficit induced by NBQX in the two behavioural procedures. In biochemical studies performed on rat hippocampus after the retention tests, we found that learning increased the membrane levels of AMPA receptor GluR1 and GluR2/3 subunits, as well as the phosphorylated forms of GluR1, effects that were abolished by NBQX administration before the training session. Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression. Moreover, administration of WAY-100635 before object recognition training improved recognition memory 24h later and potentiated the learning-associated increase in AMPA receptor subunits. The results support the proposed utility of 5-HT1A antagonists in the treatment of cognitive disorders.
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PMID:Opposing effects of AMPA and 5-HT1A receptor blockade on passive avoidance and object recognition performance: correlation with AMPA receptor subunit expression in rat hippocampus. 1662 Aug 83

Metabotropic glutamate receptors (mGluRs) play an important role in the initiation of ictal discharges by participating in the interictal-ictal transition, and may play a crucial role in recruiting normal brain tissue into synchronized discharges, thereby facilitating propagation of seizure activity. In this article we present a review of mGluRs and epilepsy studies. Structural features of mGluRs offer multiple possibilities for synthetic compounds to modulate their activity, and for many reasons these compounds are good candidates for therapeutic applications. Group I mGluRs enhance excitatory transmission as much as groups II and III mGluRs can modulate those effects. Finally, main avenues to induce epileptogenesis are considered: activation of Ca2+ channels and Ca2+/CaMKII cascade, overexpression of AMPA and/or KA receptors, enhanced NMDARs function, activation of protooncogenes leading to a steady epileptogenic state, enhancement of INaP currents, blockade of A and/or M K(+) currents, calcium channelopathies, diminished number of GABARs or functions, and down-regulation of glutamate transporters. Deregulation of mGluR signaling functions including deficits in groups II and III mGluRs or hyperactivation of group I mGluRs may occur in some forms of epilepsy, therefore targeting these mechanisms with specific pharmacological tools could provide new developments for original therapeutic approaches.
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PMID:Metabotropic glutamate receptors and epilepsy. 1669 14

Recent studies have demonstrated that activation of enzymes can be observed in living cells in response to stimulation with neurotransmitters, hormones, growth factors, and so forth. Thus, the activation of enzymes was shown to be closely related to the dynamic states of various cell functions. The development of new experimental methodologies has enabled researchers to study the molecular basis of neuronal plasticity in living cells. In 1973, Bliss and his associates identified the phenomena of long-term potentiation (LTP). Since it was thought to be a model for neuronal plasticity such as learning and memory, its molecular mechanism has been extensively investigated. The mechanism was found to involve a signal transduction cascade that includes release of glutamate, activation of the NMDA glutamate receptors, Ca(2+) entry, and activations of Ca(2+)/calmodulin-dependent protein kinases (CaM kinases) II and IV and mitogen-activated protein kinase (MAPK). Consequently, AMPA glutamate receptors were activated by phosphorylation by CaM kinase II, resulting in an increase of Ca(2+) entry into postsynaptic neurons. Furthermore, activation of CaM kinase IV and MAPK increased phosphorylation of CREB (cyclic AMP response element binding protein) and expression of c-Fos by stimulation of gene expression. These results suggest that LTP induction and maintenance would be models of short- and long-term memory, respectively.
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PMID:Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. 1679 59

PSD-95 and SAP97 are scaffolding proteins that have been implicated in regulating AMPA receptor incorporation and function at synapses. Gain- and loss-of-function approaches, however, have generated conflicting results. To minimize adaptations during development and potential dominant-negative effects of overexpression, we have combined silencing of endogenous PSD-95 in mature neurons with heterologous expression of specific SAP97 or PSD-95 isoforms. We find that both PSD-95 and SAP97 contain alternative N termini expressing either double cysteines that normally are palmitoylated (alpha-isoforms) or an L27 domain (beta-isoforms). Whereas alpha-isoforms of PSD-95 and SAP97 influence AMPA receptor-mediated synaptic strength independent of activity, the effects of beta-isoforms are regulated by activity in a CaMKII-dependent manner. Importantly, the synaptic effects of the beta-isoforms are masked by the endogenous alpha-isoform of PSD-95. These results demonstrate that the different N termini of the predominant endogenous forms of PSD-95 (alpha-isoform) and SAP97 (beta-isoform) govern their role in regulating synaptic function.
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PMID:Alternative N-terminal domains of PSD-95 and SAP97 govern activity-dependent regulation of synaptic AMPA receptor function. 1681 35

Synaptic plasticity in CA1 hippocampal neurons depends on Ca2+ elevation and the resulting activation of calmodulin-dependent enzymes. Induction of long-term depression (LTD) depends on calcineurin, whereas long-term potentiation (LTP) depends on Ca2+/calmodulin-dependent protein kinase II (CaMKII). The concentration of calmodulin in neurons is considerably less than the total concentration of the apocalmodulin-binding proteins neurogranin and GAP-43, resulting in a low level of free calmodulin in the resting state. Neurogranin is highly concentrated in dendritic spines. To elucidate the role of neurogranin in synaptic plasticity, we constructed a computational model with emphasis on the interaction of calmodulin with neurogranin, calcineurin, and CaMKII. The model shows how the Ca2+ transients that occur during LTD or LTP induction affect calmodulin and how the resulting activation of calcineurin and CaMKII affects AMPA receptor-mediated transmission. In the model, knockout of neurogranin strongly diminishes the LTP induced by a single 100 Hz, 1 s tetanus and slightly enhances LTD, in accord with experimental data. Our simulations show that exchange of calmodulin between a spine and its parent dendrite is limited. Therefore, inducing LTP with a short tetanus requires calmodulin stored in spines in the form of rapidly dissociating calmodulin-neurogranin complexes.
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PMID:Role of the neurogranin concentrated in spines in the induction of long-term potentiation. 1683 80


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