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Published online January 7, 2008
doi:10.1083/jcb.200710107
The Journal of Cell Biology, Vol. 180, No. 1, 173-186
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Lowe et al.
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Article

 Voltage-gated Nav channel targeting in the heart requires an ankyrin-G–dependent cellular pathway

John S. Lowe1, Oleg Palygin2, Naina Bhasin1, Thomas J. Hund1, Penelope A. Boyden3, Erwin Shibata2, Mark E. Anderson1,2, and Peter J. Mohler1,2

1 Department of Internal Medicine, Division of Cardiology, and 2 Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, IA 52242
3 Department of Pharmacology, Center for Molecular Therapeutics, Columbia University, New York, NY 10032

Correspondence to Peter J. Mohler: peter-mohler{at}uiowa.edu

Voltage-gated Nav channels are required for normal electrical activity in neurons, skeletal muscle, and cardiomyocytes. In the heart, Nav1.5 is the predominant Nav channel, and Nav1.5-dependent activity regulates rapid upstroke of the cardiac action potential. Nav1.5 activity requires precise localization at specialized cardiomyocyte membrane domains. However, the molecular mechanisms underlying Nav channel trafficking in the heart are unknown. In this paper, we demonstrate that ankyrin-G is required for Nav1.5 targeting in the heart. Cardiomyocytes with reduced ankyrin-G display reduced Nav1.5 expression, abnormal Nav1.5 membrane targeting, and reduced Na+ channel current density. We define the structural requirements on ankyrin-G for Nav1.5 interactions and demonstrate that loss of Nav1.5 targeting is caused by the loss of direct Nav1.5–ankyrin-G interaction. These data are the first report of a cellular pathway required for Nav channel trafficking in the heart and suggest that ankyrin-G is critical for cardiac depolarization and Nav channel organization in multiple excitable tissues.

Abbreviation used in this paper: shRNA, small hairpin RNA.


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