CaMKll is a tightly regulated cardiac enzyme implicated in the development of heart failure, arrhythmias and cardiomyocyte survival. This proposal uses a unique set of genetically modified transgenic and knockout mice in which CaMKII5, the predominant CaMKII isoform in the heart, and its splice variants CaMKII6B and 5c are deleted or overexpressed so as to allow independent evaluation of their functions and effects at the nucleus, SR, and mitochondria. The proposal tests the hypothesis that the localization and molecular interactions of CaMKII create platforms which specify whether CaMKII activation effects changes in Ca handling, gene expression or mitochondrial cell death pathways. The proposed experiments study both in vivo function and in vitro cellular mechanisms.
In Aim #1 we ask whether there Is specificity in the activation of CaMKII In different subcellular compartments depending on the intervention.
Sub aims determine if exclusively expressed CaMKII6B and 6c are differentially activated, in which subcellular compartments CaMKII is activated, whether CaMKII is translocated following its activation, and whether the minor cardiac isoforms, CaMKlip and CaMKlly , alter CaMKIIS activation.
In Aim #2 we explore the consequences of subtype or compartmentalized CaMKII activity on cardiac function.
Sub aims determine whether nuclear CaMKII mediates hypertrophy in response to ET-1, whether SR localized CaMKII and its effects on RyR2 phosphorylation mediate heart failure (HF) development, and whether CaMKIISs and 5c subserve distinct and opposing functions in ischemia induced injury and HF.
Aim #3 investigates the proteins that interact with, are phosphorylated by and are transcriptionally activated in response to cardiac CaMKIISsand 6c activation using proteomics and gene arrays to explore distinct partners, phosphorylation targets and transcriptional programs.
The final Aim #4 addresses how CaMKII regulates mitochondrial cell survival.
Sub aims consider whether CaMKIISe and 5c differentially affect mitochondrial cell death pathways, if this occurs through proteins that are phosphorylated or transcriptionally regulated by CaMKII, and whether CaMKII directly associates with mitochondria to regulate mitochondrial function. The significance of this work comes from the increasing and compelling evidence that CaMKII is a novel potential therapeutic target for treatment of HF. Distinguishing the maladaptive and adaptive roles of CaMKII subtype activation at different cellular compartments and defining its targets is a means of understanding how to confer drug specificity.

Public Health Relevance

Cardiac disease and development of heart failure are amongst the primary causes of death in the nation and worldwide. We have discovered that a particular molecule called CaM kinase II is regulated in response to cardiac stress and injury and is a major factor in heart failure development. Here we seek to further understand what makes this enzyme active, where in the cell it works, and which of its effects would be useful therapeutic targets.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of California Davis
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Yuen, Garrick K; Galice, Samuel; Bers, Donald M (2017) Subcellular localization of Na/K-ATPase isoforms in ventricular myocytes. J Mol Cell Cardiol 108:158-169
Burel, Sophie; Coyan, Fabien C; Lorenzini, Maxime et al. (2017) C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. J Biol Chem 292:17431-17448
Kanaporis, Giedrius; Blatter, Lothar A (2017) Membrane potential determines calcium alternans through modulation of SR Ca2+ load and L-type Ca2+ current. J Mol Cell Cardiol 105:49-58
Bovo, Elisa; Huke, Sabine; Blatter, Lothar A et al. (2017) The effect of PKA-mediated phosphorylation of ryanodine receptor on SR Ca2+ leak in ventricular myocytes. J Mol Cell Cardiol 104:9-16
Bers, Donald M (2017) CALMing Down Arrhythmogenic Calmodulinopathies via a Precision Medicine Approach. Circ Res 120:3-4
Lang, Di; Sato, Daisuke; Jiang, Yanyan et al. (2017) Calcium-Dependent Arrhythmogenic Foci Created by Weakly Coupled Myocytes in the Failing Heart. Circ Res 121:1379-1391
Ma, Xiaolong; Chen, Chao; Veevers, Jennifer et al. (2017) CRISPR/Cas9-mediated gene manipulation to create single-amino-acid-substituted and floxed mice with a cloning-free method. Sci Rep 7:42244
Dewenter, Matthias; Neef, Stefan; Vettel, Christiane et al. (2017) Calcium/Calmodulin-Dependent Protein Kinase II Activity Persists During Chronic ?-Adrenoceptor Blockade in Experimental and Human Heart Failure. Circ Heart Fail 10:e003840
Pereira, Laƫtitia; Bare, Dan J; Galice, Samuel et al. (2017) ?-Adrenergic induced SR Ca2+ leak is mediated by an Epac-NOS pathway. J Mol Cell Cardiol 108:8-16
Blatter, Lothar A (2017) The intricacies of atrial calcium cycling during excitation-contraction coupling. J Gen Physiol 149:857-865

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