A genetic approach to defining the cardiac roles of the KCNE2 potassium channel subunit

Project: Research

Investigators

  • Geoffrey W Abbott (PI)

Description

Inherited long QT syndrome (LQTS) and its more common counterpart acquired LQTS are potentially lethal cardiac rhythm disturbances caused by impaired ventricular repolarization. Mutations in a variety of ion channel pore-forming subunits are known to cause inherited LQTS, and likewise a range of medicines, some commonly prescribed, cause acquired LQTS - primarily by blockade of the hERG potassium channel. Inherited sequence variants in the gene for KCNE2, a promiscuous K+ channel ancillary subunit expressed in several tissues including heart, associate with inherited and acquired LQTS. Because KCNE2 can regulate several cardiac K+ channels in vitro, including hERG, KCNQ1, Kv4.2 and Kv4.3, the molecular etiology of KCNE2-associated arrhythmias will remain unclear until its precise role in cardiac physiology is determined. This issue is crucial for human health because some common KCNE2 polymorphisms increase susceptibility to KCNE2-hERG blockade by commonly-prescribed medications and KCNE2 also alters the pharmacology of other potential cardiac partners. Thus the future design of cardiac-safe drugs demands knowledge of the precise molecular correlates of cardiac channels. Here, we generated a kcne2 (-/-) mouse facilitating a genetic approach to probing cardiac roles of kcne2. We propose two Specific Aims to elucidate whether kcne2 regulates key cardiac repolarization currents - Ito (Kv4 channels); IKs (KCNQ1) IKr (ERG), and IK,slow (Kv1.5) - as follows: 1. Determine the mechanisms by which whether kcne2 regulates IK,slow in adult mouse ventricles. Our preliminary data show that kcne2 disruption impairs 4-aminopyridine-sensitive IK,slow current in adult murine ventricles, suggesting a previously unreported complex, Kv1.5-kcne2, occurs in vivo. We propose to test this hypothesis using native co-immunoprecipitation and localization analyses, combined with heterologous patch-clamp studies of this putative complex.2. Determine whether kcne2 regulates Ito, IK,slow, IKs and IKr in neonatal mouse ventricles. Using an approach similar to that in Aim 1 combined with ECG and native myocyte recordings, we propose to test the hypothesis that kcne2 regulates Ito, IK,slow, IKs and IKr currents in neonatal mouse ventricles. The presence of IKs and IKr, crucial for human ventricular repolarization, in murine ventricles at age 1-3 days offers the chance to study the role of kcne2 in regulating these currents in a native cardiac system, using neonatal kcne2 (-/-) mice.
Award amount$198,000.00
Award date07/01/2008
Program typeGrant-in-Aid
Award ID0855756D
Effective start/end date07/01/200806/30/2011
StatusFinished