The molecular basis of CaMKII function in synaptic and behavioural memory

Lisman, John; Schulman, Howard; Cline, Hollis T.

doi:10.1038/nrn753

Cited by 1,705 publications

(1,554 citation statements)

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“…Other regulators of NR2B include the calcium-calmodulin-dependent protein kinase II (CAMKII) dependent phosphorylation (23). Recently, Guilland (24) demonstrated that the CAMKII dependent phosphorylation of Ser 1029 on KIF17 is responsible for the ultimate release of NR2B, the KIF17 cargo.…”

Section: Commentmentioning

confidence: 99%

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Roberson

Toso

Abebe

et al. 2008

American Journal of Obstetrics and Gynecology

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Objective-Down syndrome (DS) a major cause of mental retardation affects 1/800 newborns. Mouse models for Down syndrome have been studied and found to have developmental and learning deficits, including the Ts65Dn (DS) mouse model. NMDA receptor NR2B subunit enhances synaptic plasticity. Upregulation of KIF17, a motor protein which transports NR2B to the synaptic region parallels upregulation of synaptic NR2B. Down regulation of KIF17 reflects upregulation of less plastic NR2A subunit. We evaluated NR2B, NR2A and KIF17 in Ts65Dn and control mice.Study Design-Ts65Dn (4) and control (4), adult brains were collected, NR2A, NR2B and KIF17 measured by western blot and quantified using NIH Image software. Comparisons were made using ANOVA, P<0.05 was considered significant.Results-There was a significant decrease in KIF17 (P=0.04) level in Ts65Dn mice as compared to the control animals but there were no significant differences in the levels of NR2A (P=0.79) and NR2B (P=0.96).Conclusion-The significant decrease of KIF17 inTs65Dn animals may in part mediate cognitive defects in DS.

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Section: Commentmentioning

confidence: 99%

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Roberson

Toso

Abebe

et al. 2008

American Journal of Obstetrics and Gynecology

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“…substrates that coordinates a variety of neuronal functions such as gene expression, membrane excitability, and neuronal transmission (Lisman et al, 2002). Multiple isoforms of CaMKII exist and the a isoform is abundantly expressed in forebrain neurons (Lisman et al, 2002).…”

Section: Cocaine-induced and D1 Receptor-mediated Gene Expression D Zmentioning

confidence: 99%

“…Multiple isoforms of CaMKII exist and the a isoform is abundantly expressed in forebrain neurons (Lisman et al, 2002). Together, changes in the expression of these molecules can change the responsiveness of the D1 receptor-expressing neurons to further neuronal stimulation.…”

Section: Cocaine-induced and D1 Receptor-mediated Gene Expression D Zmentioning

confidence: 99%

“…CaMKII is activated in response to increases in intracellular calcium levels and it can modulate synaptic plasticity both pre-and postsynaptically (Lisman et al, 2002). In the postsynaptic density, CaMKII can directly interact with and phosphorylate many proteins, including the N-methyl-D-aspartate receptor 2B subunit and a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor 1, both of which mediate excitatory neurotransmission (Yoshimura et al, 2000;Lisman et al, 2002). The D1 receptor-dependent change in CaMKIIa expression following repeated cocaine injections can thus change neurotransmission in the striatum.…”

Section: Intracellular Signaling Moleculesmentioning

confidence: 99%

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Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Zhang

Tang

et al. 2005

Neuropsychopharmacol

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Drug addiction involves compulsive drug-seeking and drug-taking despite known adverse consequences. The enduring nature of drug addiction suggests that repeated exposure to abused drugs leads to stable alterations that likely involve changes in gene expression in the brain. The dopamine D1 receptor has been shown to mediate the long-term behavioral effects of cocaine. To examine how the persistent behavioral effects of cocaine correlate with underlying changes in gene expression, we have used D1 receptor mutant and wild-type mice to identify chronic cocaine-induced gene expression changes mediated via the D1 receptors. We focused on the caudoputamen and nucleus accumbens, two key brain regions that mediate the long-term effects of cocaine. Our analyses demonstrate that repeated cocaine administration induces changes in the expression of 109 genes, including those encoding the stromal cell-derived factor 1, insulin-like growth factor binding protein 6, sigma 1 receptor, regulators of G-protein signaling protein 4, Wnt1 responsive Cdc42 homolog, Ca 2 þ /calmodulin-dependent protein kinase II a subunit, and cyclin D2, via the D1 receptors. Moreover, the seven genes contain AP-1 binding sites in their promoter regions. These results suggest that genes encoding certain extracellular factors, membrane receptors and modulators, and intracellular signaling molecules, among others, are regulated by cocaine via the D1 receptor, and these AP-1 transcription complex-regulated genes might contribute to persistent cocaine-induced behavioral changes.

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“…While the phenomenon of sustained EADs postmitochondrial repolarization in cardiomyocytes needs further experimental verification, it may indeed occur in cells undergoing oxidative stress such as ischemia reperfusion, as a result of the specific property of CaMKII as “a memory molecule.”60 The memory refers to the autophosphorylation‐mediated sustained CaMKII activation even after the dissociation of Ca 2+ /CaM or the fall of Ca 2+ concentration to baseline levels, which is essential for memory storage in the brain. Recently, Song et al61 showed that short‐term (5 minutes) ROS exposure caused persistent (more than 60 minutes) activation of I CaL in isolated rat cardiomyocytes, likely via the oxidative stress–induced sustained CaMKII activation, indicating that CaMKII may act as a redox‐sensitive “memory molecule” in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

Yang

Erñst

Song

et al. 2018

JAHA

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BackgroundOxidative stress–mediated Ca2+/calmodulin‐dependent protein kinase II (CaMKII) phosphorylation of cardiac ion channels has emerged as a critical contributor to arrhythmogenesis in cardiac pathology. However, the link between mitochondrial‐derived reactive oxygen species (mdROS) and increased CaMKII activity in the context of cardiac arrhythmias has not been fully elucidated and is difficult to establish experimentally.Methods and ResultsWe hypothesize that pathological mdROS can cause erratic action potentials through the oxidation‐dependent CaMKII activation pathway. We further propose that CaMKII‐dependent phosphorylation of sarcolemmal slow Na+ channels alone is sufficient to elicit early afterdepolarizations. To test the hypotheses, we expanded our well‐established guinea pig cardiomyocyte excitation‐contraction coupling, mitochondrial energetics, and ROS‐induced‐ROS‐release model by incorporating oxidative CaMKII activation and CaMKII‐dependent Na+ channel phosphorylation in silico. Simulations show that mdROS mediated‐CaMKII activation elicits early afterdepolarizations by augmenting the late Na+ currents, which can be suppressed by blocking L‐type Ca2+ channels or Na+/Ca2+ exchangers. Interestingly, we found that oxidative CaMKII activation–induced early afterdepolarizations are sustained even after mdROS has returned to its physiological levels. Moreover, mitochondrial‐targeting antioxidant treatment can suppress the early afterdepolarizations, but only if given in an appropriate time window. Incorporating concurrent mdROS‐induced ryanodine receptors activation further exacerbates the proarrhythmogenic effect of oxidative CaMKII activation.ConclusionsWe conclude that oxidative CaMKII activation–dependent Na channel phosphorylation is a critical pathway in mitochondria‐mediated cardiac arrhythmogenesis.

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The molecular basis of CaMKII function in synaptic and behavioural memory

Cited by 1,705 publications

References 123 publications

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

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The molecular basis of CaMKII function in synaptic and behavioural memory

Cited by 1,705 publications

References 123 publications

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Altered expression of KIF17, a kinesin motor protein associated with NR2B trafficking, may mediate learning deficits in a Down syndrome mouse model

Repeated Cocaine Administration Induces Gene Expression Changes through the Dopamine D1 Receptors

Mitochondrial‐Mediated Oxidative Ca 2+ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study

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Mitochondrial‐Mediated Oxidative Ca ²⁺ /Calmodulin‐Dependent Kinase II Activation Induces Early Afterdepolarizations in Guinea Pig Cardiomyocytes: An In Silico Study