Normal cardiac excitability depends on the coordinated biophysical activity of specific ion channels and transporters on the plasma membrane. Over the past decade, gene mutations that affect ion channel biophysical activity have been linked with fatal human arrhythmias. Recently, another class of gene mutations has been identified that alters local coupling of ion channels with cytoskeletal and regulatory proteins. It is clear that ion channel function depends on normal biophysical properties AND proper localization within specialized membrane domains. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a multifunctional serine/threonine kinase with diverse cardiac roles including regulation of excitation contraction, transcription, and apoptosis. Recent findings demonstrate that local organization of CaMKII within excitable cells is essential for regulation of ion channels and receptors involved in critical cell functions such as excitation contraction coupling and long term potentiation. We have generated exciting new preliminary data that identifies a novel targeting mechanism for CaMKII to the cardiomyocyte intercalated disc. Specifically, we have identified beta lV-spectrin as a novel intercalated disc CaMKII anchoring protein that complexes CaMKII with Nav1.5, the primary voltage gated Na+ channel in heart. We have generated innovative molecular, biochemical, and mathematical tools to test our central hypothesis that a novel spectrin-based intercalated disc protein complex is critical for organizing CaMKII in context with target proteins including Nav1.5. We propose the following aims:
Specific Aim 1. Determine the molecular mechanism by which beta lV-spectrin targets CaMKII to the cardiac intercalated disc.
Specific Aim 2. Define the role of beta lV-spectrin in the local organization of CaMKII with Nav1,5 at the cardiac intercalated disc.
Specific Aim 3. Define the role of spectrin/CaMKII signaling complex in the local regulation of primary cardiomyocyte Nav channel function, myocyte electrical activity and arrhythmogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
5R00HL096805-04
Application #
8322779
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lathrop, David A
Project Start
2010-09-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
4
Fiscal Year
2012
Total Cost
$249,000
Indirect Cost
$85,721
Name
Ohio State University
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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