title: CaMKIIδ and cardiomyocyte Ca(2+) signalling new perspectives on splice variant targeting.
abstract: Control of cardiomyocyte cytosolic Ca(2+) levels is crucial in determining inotropic status and ischemia/reperfusion stress response. Responsive to fluctuations in cellular Ca(2+), Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a serine/threonine kinase integral to the processes regulating cardiomyocyte Ca(2+) channels/transporters. CaMKII is primarily expressed either in the δB or δC splice variant forms, which may mediate differential influences on cardiomyocyte function and pathological response mechanisms. Increases in myocyte Ca(2+) levels promote the binding of a Ca(2+)/calmodulin complex to CaMKII, to activate the kinase. Activity is also maintained through a series of post-translational modifications within a critical region of the regulatory domain of the protein. Recent data indicate that the post-translational modification status of CaMKIIδB/δC variants may have an important influence on reperfusion outcomes. This study provided the first evidence that the specific type of CaMKII post-translational modification has a role in determining target selectivity of downstream Ca(2+) transporters. The study was also able to demonstrate that the phosphorylated form of CaMKII closely co-localizes with CaMKIIδB in the nuclear/myofilament fraction, contrasting with a co-enrichment of oxidized CaMKII in the membrane fraction with CaMKIIδC . It has also been possible to conclude that a hyper-phosphorylation of CaMKII (Thr287) in reperfused hearts represents a hyper-activation of the CaMKIIδB , which exerts anti-arrhythmic actions through an enhanced capacity to selectively increase sarcoplasmic reticulum Ca(2+) uptake and maintain cytosolic Ca(2+) levels. This suggests that suppression of global CaMKIIδ may not be an efficacious approach to developing optimal pharmacological interventions for the vulnerable heart.
authors.affiliation: Department of Physiology, University of Melbourne, Victoria, Australia.
authors.forename: James R
authors.initials: JR
authors.lastname: Bell
authors.affiliation: Department of Physiology, University of Melbourne, Victoria, Australia.
authors.forename: Antonia J A
authors.initials: AJ
authors.lastname: Raaijmakers
authors.affiliation: Department of Physiology, University of Melbourne, Victoria, Australia.
authors.forename: Johannes V
authors.initials: JV
authors.lastname: Janssens
authors.affiliation: Department of Physiology, University of Melbourne, Victoria, Australia.
authors.forename: Lea M D
authors.initials: LM
authors.lastname: Delbridge
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D004789:Enzyme Activation; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology
chemical_list: D020033:Protein Isoforms; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: Ca2+ regulation; Ca2+/calmodulin-dependent protein kinase II (CaMKII); cardiomyocyte; gender medicine; ischemia/reperfusion; post-translational modification; splice variant