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Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

ABSTRACT: Calcium-calmodulin dependent protein kinase II? (CaMKII?) is an important regulator of cardiac electrophysiology, calcium (Ca) balance, contraction, transcription, arrhythmias and progression to heart failure. CaMKII is readily activated at mouths of dyadic cleft Ca channels, but because of its low Ca-calmodulin affinity and presumed immobility it is less clear how CaMKII gets activated near other known, extra-dyad targets. CaMKII is typically considered to be anchored in cardiomyocytes, but while untested, mobility of active CaMKII could provide a mechanism for broader target phosphorylation in cardiomyocytes. We therefore tested CaMKII mobility and how this is affected by kinase activation in adult rabbit cardiomyocytes. We measured translocation of both endogenous and fluorescence-tagged CaMKII using immunocytochemistry, fluorescence recovery after photobleach (FRAP) and photoactivation of fluorescence. In contrast to the prevailing view that CaMKII is anchored near its myocyte targets, we found CaMKII to be highly mobile in resting myocytes, which was slowed by Ca chelation and accelerated by pacing. At low [Ca], CaMKII was concentrated at Z-lines near the dyad but spread throughout the sarcomere upon pacing. Nuclear exchange of CaMKII was also enhanced upon pacing- and heart failure-induced chronic activation. This mobilization of active CaMKII and its intrinsic memory may allow CaMKII to be activated in high [Ca] regions and then move towards more distant myocyte target sites.

SUBMITTER: Wood BM

PROVIDER: S-EPMC6279589 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

Wood Brent M BM Simon Mitchell M Galice Samuel S Alim Chidera C CC Ferrero Maura M Pinna Natalie N NN Bers Donald M DM Bossuyt Julie J

Journal of molecular and cellular cardiology 20181012

Calcium-calmodulin dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac electrophysiology, calcium (Ca) balance, contraction, transcription, arrhythmias and progression to heart failure. CaMKII is readily activated at mouths of dyadic cleft Ca channels, but because of its low Ca-calmodulin affinity and presumed immobility it is less clear how CaMKII gets activated near other known, extra-dyad targets. CaMKII is typically considered to be anchored in cardiomyocytes, but whi ...[more]

PMID: 30321537

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Project description:Compromised mitophagy and mitochondrial homeostasis are major contributors for the etiology of cardiac aging, although the precise underlying mechanisms remains elusive. Shank3, a heart-enriched protein, has recently been reported to regulate aging-related neurodegenerative diseases. This study aimed to examine the role of Shank3 in the pathogenesis of cardiac senescence and the possible mechanisms involved. Cardiac-specific conditional Shank3 knockout (Shank3CKO) mice were subjected to natural aging. Mitochondrial function and mitophagy activity were determined in vivo, in mouse hearts and in vitro, in cardiomyocytes. Here, we showed that cardiac Shank3 expression exhibited a gradual increase during the natural progression of the aging, accompanied by overtly decreased mitophagy activity and a decline in cardiac function. Ablation of Shank3 promoted mitophagy, reduced mitochondria-derived superoxide (H2O2 and O2•-) production and apoptosis, and protected against cardiac dysfunction in the aged heart. In an in vitro study, senescent cardiomyocytes treated with D-gal exhibited reduced mitophagy and significantly elevated Shank3 expression. Shank3 knock-down restored mitophagy, leading to increased mitochondrial membrane potential, decreased mitochondrial oxidative stress, and reduced apoptosis in senescent cardiomyocytes, whereas Shank3 overexpression mimicked D-gal-induced mitophagy inhibition and mitochondrial dysfunction in normally cultured cardiomyocytes. Mechanistically, the IP assay revealed that Shank3 directly binds to CaMKII, and this interaction was further increased in the aged heart. Enhanced Shank3/CaMKII binding impedes mitochondrial translocation of CaMKII, resulting in the inhibition of parkin-mediated mitophagy, which ultimately leads to mitochondrial dysfunction and cardiac damage in the aged heart. Our study identified Shank3 as a novel contributor to aging-related cardiac damage. Manipulating Shank3/CaMKII-induced mitophagy inhibition could thus be an optional strategy for therapeutic intervention in clinical aging-related cardiac dysfunctions.

Dataset Information

Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

Publications

Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

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