Changes in the repolarization properties of cardiac muscle frequently underlie the increased susceptibility to ventricular arrhythmias in a variety of heart diseases, but the control of cardiac repolarization is incompletely understood. Abnormalities of repolarization resulting in action potential duration prolongation or shortening can be pro-arrhythmic. Multiple different ion channels in cardiomyocytes impact action potential repolarization, and the diversity of ion channels and regulatory pathways involved in repolarization is highlighted by the association of at least 13 distinct genes with the inherited long QT syndrome which is due to delayed repolarization. For example, mutations in the caveolin-3 gene (CAV3) have been implicated as one cause of the inherited Long QT syndrome (LQTS). Cav-3 is an essential scaffolding protein required for the formation of specialized membrane microdomains in cells referred to as caveolae which are home to multiple signaling molecules and ion channel proteins. Preliminary data presented in this application show that genetic ablation of caveolin-3 in the mouse heart dramatically prolongs cardiac repolarization. The proposed research will test the hypothesis that cardiac caveolae provide integrated regulation of cardiac repolarization by controlling the density and functional properties of specifc ion channels. Using both genetically engineered mouse models with cardiac-specific regulation of Cav-3 expression as well as human iPS cell-cardiomyocyte models, the proposal will examine the role of caveolae in the regulation of cardiac repolarization in three specific aims: 1) Determine the impact of changes in the abundance of Cav-3 in cardiomyocytes on the density of caveolae and on cardiac repolarization;2) Evaluate the impact of changes in Cav-3 abundance and LQTS-associated Cav-3 mutations on the density and biophysical properties of voltage-gated potassium currents;and 3) Determine how wild type Cav-3 and LQTS-associated mutations of Cav-3 regulate the density and properties of ICa,L. These studies will provide mechanistic new insights into the control of cardiac repolarization and abnormalities in disease which can result in arrhythmias.

Public Health Relevance

Cardiac arrhythmias can be life threatening and are manifestations of many different forms of heart disease. Understanding the cellular mechanisms that regulate the electrical signals in the heart will provide new insights for therapy and prevention of cardiac arrhythmias. DESCRIPTION (provided by applicant): Changes in the repolarization properties of cardiac muscle frequently underlie the increased susceptibility to ventricular arrhythmias in a variety of heart diseases, but the control of cardiac repolarization is incompletely understood. Abnormalities of repolarization resulting in action potential duration prolongation or shortening can be pro-arrhythmic. Multiple different ion channels in cardiomyocytes impact action potential repolarization, and the diversity of ion channels and regulatory pathways involved in repolarization is highlighted by the association of at least 13 distinct genes with the inherited long QT syndrome which is due to delayed repolarization. For example, mutations in the caveolin-3 gene (CAV3) have been implicated as one cause of the inherited Long QT syndrome (LQTS). Cav-3 is an essential scaffolding protein required for the formation of specialized membrane microdomains in cells referred to as caveolae which are home to multiple signaling molecules and ion channel proteins. Preliminary data presented in this application show that genetic ablation of caveolin-3 in the mouse heart dramatically prolongs cardiac repolarization. The proposed research will test the hypothesis that cardiac caveolae provide integrated regulation of cardiac repolarization by controlling the density and functional properties of specifc ion channels. Using both genetically engineered mouse models with cardiac-specific regulation of Cav-3 expression as well as human iPS cell-cardiomyocyte models, the proposal will examine the role of caveolae in the regulation of cardiac repolarization in three specific aims: 1) Determine the impact of changes in the abundance of Cav-3 in cardiomyocytes on the density of caveolae and on cardiac repolarization;2) Evaluate the impact of changes in Cav-3 abundance and LQTS-associated Cav-3 mutations on the density and biophysical properties of voltage-gated potassium currents;and 3) Determine how wild type Cav-3 and LQTS-associated mutations of Cav-3 regulate the density and properties of ICa,L. These studies will provide mechanistic new insights into the control of cardiac repolarization and abnormalities in disease which can result in arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL078878-05
Application #
8514364
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2004-12-01
Project End
2017-04-30
Budget Start
2013-08-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$365,273
Indirect Cost
$120,134
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Gao, Ge; Xie, An; Zhang, Jianhua et al. (2013) Unfolded protein response regulates cardiac sodium current in systolic human heart failure. Circ Arrhythm Electrophysiol 6:1018-24
Best, Jabe M; Kamp, Timothy J (2012) Different subcellular populations of L-type Ca2+ channels exhibit unique regulation and functional roles in cardiomyocytes. J Mol Cell Cardiol 52:376-87
Best, Jabe M; Foell, Jason D; Buss, Courtney R et al. (2011) Small GTPase Rab11b regulates degradation of surface membrane L-type Cav1.2 channels. Am J Physiol Cell Physiol 300:C1023-33
Best, Jabe M; Kamp, Timothy J (2010) A sympathetic model of L-type Ca2+ channel-triggered arrhythmias. Am J Physiol Heart Circ Physiol 298:H3-4
Balijepalli, Ravi C; Kamp, Timothy J (2008) Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol 98:149-60