Voltage-gated potassium (Kv) channels repolarize excitable cells such as cardiac myocytes. Dysfunction of cardiac myocyte Kv channels causes life-threatening cardiac arrhythmias, but these channels are also useful antiarrhythmic drug targets. Thus, it is essential to understand their function, regulation and molecular composition, and determine how these differ regionally and between species. The current proposal draws from our preceding decade of work on cloning and defining the diverse physiological roles of members of the KCNE family of single- transmembrane-domain Kv channel ancillary subunits. Following our previous findings that KCNE2 mutations associate with inherited and acquired human ventricular arrhythmias, more recently we generated the kcne2 (-/-) mice line and used it to determine the primary roles of KCNE2 in adult murine ventricles - modulation of two Kv channels and their native current correlates: Kv4.2 (Ito,f) and, unexpectedly, Kv1.5 (IK,slow1). We also defined a new role for KCNE1, as an endocytic chaperone of the KCNQ1 a subunit, and found that both KCNE1 and KCNE2 can influence the a subunit composition of functional Kv channels. KCNQ1, KCNE1 and KCNE2 mutations associate with both atrial and ventricular arrhythmias. Kv1.5 mutations associate with atrial fibrillation (AF), and its function is relatively atrial-specific in human heart, potentially making it a useful target for atrial antiarrhythmics. Most forms of AF have no know genetic basis, and correlate with other factors such as aging, or following surgery to the heart or lungs. A fuller understanding of the native physiology of all these Kv subunits, and how they contribute to both inherited, and age-onset or post-surgery (acquired) forms of AF, is important to improving human cardiac health. Here, we propose to determine the roles of KCNE2 in atrial physiology and in the etiology of AF, utilizing kcne2 (-/-) mice (which exhibit pacing-induced AF), rabbit and swine models of post-operative AF, confirmatory experiments with human atrial tissue, and in silico multiscale atrial models. The studies comprise three Specific Aims. First, we will use a molecular approach to determine which atrial Kv complexes KCNE2 regulates, how its genetic disruption causes AF and Kv channel remodeling, how these mechanisms mirror post-operative AF in larger animals, and the role of Sp1, miR-1 and miR-133 in this remodeling. Second, we will use an electrophysiology/computer modeling approach to determine the function of KCNE2 in mouse and rabbit atria, compare the cellular functional effects arising from kcne2 genetic disruption and post-operative AF, and simulate the mechanistic basis for the resultant arrhythmias, from the cellular to the tissue level. Third, we will define the relationship between KCNE2, Kv1.5, and the intercalated discs (IDs), and determine why KCNE2 disruption prevents Kv1.5 ID targeting in the murine ventricles but not atria.

Public Health Relevance

Specific potassium channels govern cardiac repolarization to end each heart-beat in a timely fashion;inherited gene variants in the genes that encode potassium channels, including KCNQ1, KCNE1 and KCNE2, cause lethal cardiac arrhythmias in man. Atrial fibrillation, which afflicts 2.5 million people in the United States, can be caused by mutation in these genes but is more commonly associated with aging and some surgical procedures. Our proposal is designed to determine the mechanistic role of potassium channels in the atrium, focusing primarily on KCNE2, and uncover molecular events leading up to dysfunction of KCNE2 in inherited and acquired forms of atrial fibrillation, in order to facilitate future antiarrhythmic therapy and prevention strategies.

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
Krull, Holly
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
Schools of Medicine
United States
Zip Code
King, Elizabeth C; Patel, Vishal; Anand, Marie et al. (2017) Targeted deletion of Kcne3 impairs skeletal muscle function in mice. FASEB J 31:2937-2947
Abbott, Geoffrey W (2016) KCNE1 and KCNE3: The yin and yang of voltage-gated K(+) channel regulation. Gene 576:1-13
Crump, Shawn M; Hu, Zhaoyang; Kant, Ritu et al. (2016) Kcne4 deletion sex- and age-specifically impairs cardiac repolarization in mice. FASEB J 30:360-9
Lee, Soo Min; Nguyen, Dara; Anand, Marie et al. (2016) Kcne2 deletion causes early-onset nonalcoholic fatty liver disease via iron deficiency anemia. Sci Rep 6:23118
Hu, Zhaoyang; Crump, Shawn M; Zhang, Ping et al. (2016) Kcne2 deletion attenuates acute post-ischaemia/reperfusion myocardial infarction. Cardiovasc Res 110:227-37
Abbott, Geoffrey W (2015) The KCNE2 K? channel regulatory subunit: Ubiquitous influence, complex pathobiology. Gene 569:162-72
Lee, Soo Min; Nguyen, Dara; Hu, Zhaoyang et al. (2015) Kcne2 deletion promotes atherosclerosis and diet-dependent sudden death. J Mol Cell Cardiol 87:148-51
Hu, Zhaoyang; Crump, Shawn M; Anand, Marie et al. (2014) Kcne3 deletion initiates extracardiac arrhythmogenesis in mice. FASEB J 28:935-45
Hu, Zhaoyang; Kant, Ritu; Anand, Marie et al. (2014) Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death. Circ Cardiovasc Genet 7:33-42
Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L et al. (2014) KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability. Sci Signal 7:ra22

Showing the most recent 10 out of 45 publications