Voltage-gated K+ (Kv) currents are differentially distributed across the left ventricular wall. Kv4 currents are larger in left ventricular epicardial (EPI) cells than in endocardial (ENDO) cells. This non-uniform distribution of Kv4 channel function is essential for normal myocardial repolarization. We recently reported that variations in [Ca2+]i are transduced into changes in Kv4 expression through the activation of the Ca2+-sensitive phosphatase calcineurin and the transcription factor NFATc3. This led to our discovery that differential [Ca2+]i/calcineurin/NFATc3 signaling across the left ventricular free wall underlies transmural variations in Kv4 expression. However, the mechanisms underlying regional differences in [Ca2+]j, calcineurin, and NFATc3 signaling are poorly understood. The work proposed in this application employs a series of novel techniques and approaches developed by our group to address these important issues. Our preliminary data suggest that the proposed experiments are not only feasible but will provide new fundamental information regarding Kv channel regulation in the heart. The proposed work addresses three specific hypotheses. First, we will test the hypothesis that regional variations in [Ca2+]j underlie heterogeneous calcineurin activity in the ventricle. Second, we will test the hypothesis that local and global [Ca2+]i signals modulate NFAT translocation and gene expression in ventricular myocytes. We will then use these data to determine how variations in [Ca2+]j signals between ENDO and EPI cells lead to regional differences in NFAT activity. Finally, we will test the hypothesis that calcineurin/NFATc3 signaling is essential for maintaining Kv current heterogeneity in the ventricle. Taken together, this work will provide the first integrated view of calcium signaling, excitability, and contractility in the heart and significantly enhance our understanding of the basic mechanisms, which regulate Kv channel function in health and disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Schools of Medicine
United States
Zip Code
Li, Lei; Li, Jing; Drum, Benjamin M et al. (2017) Loss of AKAP150 promotes pathological remodelling and heart failure propensity by disrupting calcium cycling and contractile reserve. Cardiovasc Res 113:147-159
Vivas, Oscar; Moreno, Claudia M; Santana, Luis F et al. (2017) Proximal clustering between BK and CaV1.3 channels promotes functional coupling and BK channel activation at low voltage. Elife 6:
Gentil, Benoit J; O'Ferrall, Erin; Chalk, Colin et al. (2017) A New Mutation in FIG4 Causes a Severe Form of CMT4J Involving TRPV4 in the Pathogenic Cascade. J Neuropathol Exp Neurol 76:789-799
Nieves-Cintrón, Madeline; Hirenallur-Shanthappa, Dinesh; Nygren, Patrick J et al. (2016) AKAP150 participates in calcineurin/NFAT activation during the down-regulation of voltage-gated K(+) currents in ventricular myocytes following myocardial infarction. Cell Signal 28:733-40
Drum, Benjamin M L; Yuan, Can; Li, Lei et al. (2016) Oxidative stress decreases microtubule growth and stability in ventricular myocytes. J Mol Cell Cardiol 93:32-43
Dickson, Eamonn J; Jensen, Jill B; Vivas, Oscar et al. (2016) Dynamic formation of ER-PM junctions presents a lipid phosphatase to regulate phosphoinositides. J Cell Biol 213:33-48
Moreno, Claudia M; Dixon, Rose E; Tajada, Sendoa et al. (2016) Ca(2+) entry into neurons is facilitated by cooperative gating of clustered CaV1.3 channels. Elife 5:
Drum, Benjamin M L; Santana, Luis F (2015) The long and winding road home: how junctin and triadin find their way to the junctional SR. J Mol Cell Cardiol 81:15-7
Dixon, Rose E; Moreno, Claudia M; Yuan, Can et al. (2015) Graded Ca²?/calmodulin-dependent coupling of voltage-gated CaV1.2 channels. Elife 4:
Drum, Benjamin M L; Dixon, Rose E; Yuan, Can et al. (2014) Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8). J Mol Cell Cardiol 66:63-71

Showing the most recent 10 out of 34 publications