The broad, long-term objectives of this proposal are to determine the specific function and macromolecular structure of Kv1.5 (a voltage-dependent K+ channel alpha subunit possibly involved in repolarization of the cardiac action potential). This work is based on the hypothesis that the Kv1.5 alpha subunit is a component of a K+ channel involved in phase repolarization of the cardiac action potential (and hence functions as a receptor of anti-arrhythmic drugs with Class III action). This work is a first step in the long process of dissecting the proteins that mediate repolarizing outward current in the heart.
The Specific Aims are 1) compare the electrophysiological characteristics of delayed-rectifier K+ currents in wild-type cardiac myocytes with those from mutant animals lacking a functional Kv1.5 gene, 2) compare ambulatory electrocardiograms in mice from three genetic backgrounds (wild-type, Kv1.5-null, heterozygotic) at baseline and after exposure to drugs that modulate myocyte repolarization, and 3) determine whether the absence of Kv1.5 in vivo modulates protein and transcript levels of other alpha and/or beta subunits. Increasingly, disorders of repolarization are causally implicated in many malignant cardiac arrhythmias. These arrhythmias underlie sudden cardiac death which is a major killer of Americans today causing an estimated 400,000 deaths per year. Increasingly, we treat atrial fibrillation the commonest arrhythmia, afflicting 1 percent of persons older than 60 years old-with repolarization-active anti-arrhythmic agents. The structural basis of repolarizing current in heart is presently poorly characterized. However, the ion channels that mediate repolarizing K+ current serve as receptors for anti-arrhythmic drugs with Class III activity, one of our major weapons against these devastating arrhythmias. The research design centers on comparing physiologic parameters and biochemical features of wild-type mice with mice deficient in Kv1.5. The methods to be used are biochemical and immunological (Western blots, immunoprecipitation) and electrophysiological (patch clamping, ambulatory electrocardiography).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL003908-02
Application #
6182810
Study Section
Special Emphasis Panel (ZHL1-CSR-Y (O1))
Project Start
1999-08-15
Project End
2004-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$98,496
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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