The voltage-gated Na channel is an integral membrane protein, part of a macromolecular complex that is central to signaling in the heart and other excitable tissues. Mutations in the channel subunits underlie heritable cardiac arrhythmias, myotonias, epilepsy and autism. Regulation of the essential functions of the channel, namely conduction and gating are complex and differ among the tissue-specific isoforms. A mechanistic understanding of the molecular regulation of the channel is beginning to emerge;however, many of the relevant studies have been limited by the fact that they were performed in expression systems rather than native cells. We and others have demonstrated the importance of the carboxyl terminus (CT) in the regulation of functional expression of the channel. The CT is a hot spot for mutations that produce inherited arrhythmias and possibly cardiomyopathies. Mutations of critical structural motifs in the CT (IQ and EFL) have profound and isoform-specific effects on channel gating, trafficking and drug block. This proposal builds on the work from the prior period of support and will test the following hypotheses: 1. The CT of the Na channel is vitally important in trafficking, gating, Ca2+ sensitivity and functional regulation of the channel. 2. Structural divergence in the CT of different NaV isoforms underlies the functional variance in channel regulation. 3. Altered Na channel trafficking and function with consequent intracellular Na+ overload contributes to the development of dilated cardiomyopathy. The hypotheses will be tested with the following specific aims: 1. Characterize the functional effects, regulation and pharmacology of mutations of the CaM binding IQ motif and Ca2+ binding EFL motif and naturally occurring mutations in the CT of NaV1.5 expressed in neonatal (NRVMs) and adult ventricular myocytes (VM). 2. Characterize the structure function relationships of the proximal CT of NaV1.5 and NaV1.4. 3. Characterization of the contractile and electrophysiological phenotype of a CaM binding deficient knock-in mouse. Given the central role of the Na current in normal physiology and disease this proposal promises to further our understanding of the essential functions of this channel, pathophysiological mechanisms of diseases of excitability and the mechanism of action of clinically important drugs.

Public Health Relevance

The sodium channel is essential for normal electrical activity and contraction of the heart and muscle. Abnormal sodium channel function is characteristic of a number of heart and skeletal muscle diseases. The proposal seeks to understand the regulation of the function of this channel in health and disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050411-17
Application #
8250034
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Wang, Lan-Hsiang
Project Start
1994-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
17
Fiscal Year
2012
Total Cost
$405,900
Indirect Cost
$158,400
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Tomaselli, Gordon F (2015) Introduction to a compendium on sudden cardiac death: epidemiology, mechanisms, and management. Circ Res 116:1883-6
Kwon, Chulan; Tomaselli, Gordon F (2015) Coins of the realm in atrioventricular junction development. Circ Res 116:386-8
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Biswas, Subrata; DiSilvestre, Deborah A; Dong, Peihong et al. (2013) Mechanisms of a human skeletal myotonia produced by mutation in the C-terminus of NaV1.4: is Ca2+ regulation defective? PLoS One 8:e81063
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Aiba, Takeshi; Hesketh, Geoffrey G; Liu, Ting et al. (2010) Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes. Cardiovasc Res 85:454-63

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