Inactivation of the Myocyte Enhancer Factor-2 Repressor Histone Deacetylase-5 by Endogenous Ca2//Calmodulin-dependent Kinase II Promotes Depolarization-mediated Cerebellar Granule Neuron Survival

Linseman, Daniel A.; Bartley, Christopher M.; Le, Shoshona S.; Laessig, Tracey A.; Bouchard, Ron J.; Meintzer, Mary Kay; Li, Mingtao; Heidenreich, Kim A.

doi:10.1074/jbc.m307245200

Cited by 113 publications

(109 citation statements)

References 60 publications

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“…Chronic stress induces NMDARdependent synaptic plasticity in the NAc (Belujon and Grace, 2011;Jiang et al, 2013) as well as plasticity of NAc synaptic structures (Christoffel et al, 2011), and both of these processes have been shown to involve CaMKII in various contexts (Colbran and Brown, 2004;Huang and Hsu, 2012;Robison et al, 2013). However, as CaMKIIa is present throughout the cell and is known to regulate histone modification machinery itself (Linseman et al, 2003), speculation for a specifically synaptic role for the fluoxetine-mediated reduction in CaMKIIa expression is premature.…”

Section: Discussionmentioning

confidence: 99%

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

Robison

Vialou

Sun

et al. 2013

Neuropsychopharmacol

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Chronic social defeat stress in mice produces a susceptible phenotype characterized by several behavioral abnormalities consistent with human depression that are reversed by chronic but not acute exposure to antidepressant medications. Recent work in addiction models demonstrates that the transcription factor DFosB and protein kinase calmodulin-dependent protein kinase II (CaMKII) are co-regulated in nucleus accumbens (NAc), a brain reward region implicated in both addiction and depression models including social defeat. Previous work has also demonstrated that DFosB is induced in NAc after chronic social defeat stress or after chronic antidepressant treatment, wherein it mediates a pro-resilience or antidepressant-like phenotype. Here, using chromatin immunoprecipitation assays, we found that DFosB binds the CaMKIIa gene promoter in NAc and that this binding increases after mice are exposed to chronic social defeat stress. Paradoxically, chronic exposure to the antidepressant fluoxetine reduces binding of DFosB to the CaMKIIa promoter and reduces CaMKII expression in NAc, despite the fact that DFosB is induced under these conditions. These data suggest a novel epigenetic mechanism of antidepressant action, whereby fluoxetine induces some chromatin change at the CaMKIIa promoter, which blocks the DFosB binding. Indeed, chronic fluoxetine reduces acetylation and increases lysine-9 dimethylation of histone H3 at the CaMKIIa promoter in NAc, effects also seen in depressed humans exposed to antidepressants. Overexpression of CaMKII in NAc blocks fluoxetine's antidepressant effects in the chronic social defeat paradigm, whereas inhibition of CaMKII activity in NAc mimics fluoxetine exposure. These findings suggest that epigenetic suppression of CaMKIIa expression in NAc is behaviorally relevant and offer a novel pathway for possible therapeutic intervention in depression and related syndromes.

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Section: Discussionmentioning

confidence: 99%

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

Robison

Vialou

Sun

et al. 2013

Neuropsychopharmacol

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“…The results of the present work further substantiate HDAC4 as a specific direct substrate of CaMKII␦, based on the finding that HDAC4 phosphorylation was abolished in cardiac extracts from CaMKII␦-KO mice, whereas HDAC5 phosphorylation was unaffected. Others have reported that CaMKII induces cytosolic accumulation of both HDAC4 and HDAC5 (19,37,38). Because HDAC5 can acquire CaMKII responsiveness by oligomerization with HDAC4 (20), the nuclear export of HDAC5 in response to CaMKII signaling may reflect, at least in part, this type of indirect mechanism of HDAC5 regulation.…”

Section: Discussionmentioning

confidence: 99%

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

Backs

Neef

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

391

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Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKII␦, the major CaMKII isoform expressed in the heart, we generated CaMKII␦-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKII␦-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKII␦-null mice, underscoring the specificity of the CaMKII␦ signaling pathway for HDAC4 phosphorylation. We conclude that CaMKII␦ functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKII␦ as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.histone deacetylase 4 (HDAC4) ͉ calcium signaling ͉ excitation contraction coupling (EC coupling) ͉ thoracic aortic constriction (TAC) ͉ CaM Kinase II inhibitory peptide (AC3-I)

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“…Previous work has shown that the phosphorylation of HDAC5 can be regulated by Ca 2+ /calmodulin-dependent kinase II (CaMKII) activity in neurons (11) and by protein kinase D (PKD) in other cell types (18). To determine whether HDAC5 phosphorylation in response to ketamine is mediated by CaMKII and PKD in hippocampal neurons, we treated cells with the CaMKII inhibitor KN-62 and PKD-specific inhibitor Gö6976.…”

Section: Resultsmentioning

confidence: 99%

“…HDAC5 is highly enriched in the brain with strong expression in forebrain regions including the hippocampus, cortex, and amygdala (9). We focus here on HDAC5 because its subcellular localization is tightly regulated by neuronal activity (11)(12)(13). The class II HDAC family of transcriptional repressors, in particular HDAC5, interacts with myocyte enhancer factor 2 (MEF2) to repress target gene expression (13,14).…”

mentioning

confidence: 99%

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Choi

Lee

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II-and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamineinduced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine.ketamine | HDAC | depression | hippocampus D epression is a multifaceted illness, characterized by somatic, cognitive, and behavioral changes. All currently available antidepressants primarily act via monoaminergic neurotransmitters, such as serotonin and/or noradrenaline (1). Currently available pharmacotherapies for depression provide some relief for patients, but these agents have significant limitations (1). In this context, new antidepressants with faster onset of action and greater efficacy are needed (2).The noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown remarkable consistency in rapidly ameliorating depressive symptoms in major depressive disorder (MDD) (3). Preclinical studies have demonstrated that ketamine produces rapid antidepressant responses (within hours) (4, 5). Ketamine's antidepressant effects in rodents are associated with activation of several signaling systems including the mammalian target of rapamycin complex 1 (mTORC1) (4), brain derived neurotrophic factor (BDNF) and elongation factor 2 (EF2) kinase (5). Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects and abuse. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels.Recent studies have generated evidence that epigenetic regulation is closely involved in the pathophysiology of depression and in the therapeutic mechanisms of typical antidepressants (6, 7). In addition, reports that sodium butyrate, a histone deacetylase (HDAC) inhibitor, has antidepressant effects indicate that HDAC inhibition is sufficient to produce an antidepressant response (8). HDACs are a family of enzymes capable of repressing gene expression by removing acetyl groups from histones to produce a less accessible chromatin structure (9).Previous studies demonstrate that the...

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Inactivation of the Myocyte Enhancer Factor-2 Repressor Histone Deacetylase-5 by Endogenous Ca2//Calmodulin-dependent Kinase II Promotes Depolarization-mediated Cerebellar Granule Neuron Survival

Cited by 113 publications

References 60 publications

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

Fluoxetine Epigenetically Alters the CaMKIIα Promoter in Nucleus Accumbens to Regulate ΔFosB Binding and Antidepressant Effects

The δ isoform of CaM kinase II is required for pathological cardiac hypertrophy and remodeling after pressure overload

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

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