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J. Biol. Chem., Vol. 282, Issue 7, 4875-4883, February 16, 2007

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Targeting and Stability of Na/Ca Exchanger 1 in Cardiomyocytes Requires Direct Interaction with the Membrane Adaptor Ankyrin-B^*

Shane R. Cunha¹, Naina Bhasin, and Peter J. Mohler²

From the Departments of Internal Medicine, Division of Cardiology and Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, Iowa City, Iowa 52242

Na/Ca exchanger activity is important for calcium extrusion from the cardiomyocyte cytosol during repolarization. Animal models exhibiting altered Na/Ca exchanger expression display abnormal cardiac phenotypes. In humans, elevated Na/Ca exchanger expression/activity is linked with pathophysiological conditions including arrhythmia and heart failure. Whereas the molecular mechanisms underlying Na/Ca exchanger biophysical properties are widely studied and generally well characterized, the cellular pathways and molecular partners underlying the specialized membrane localization of Na/Ca exchanger in cardiac tissue are essentially unknown. In this report, we present the first direct evidence for a protein pathway required for Na/Ca exchanger localization and stability in primary cardiomyocytes. We define the minimal structural requirements on ankyrin-B for direct Na/Ca exchanger interactions. Moreover, using ankyrin-B mutants that lack Na/Ca exchanger binding activity, and primary cardiomyocytes with reduced ankyrin-B expression, we demonstrate that direct interaction with the membrane adaptor ankyrin-B is required for the localization and post-translational stability of Na/Ca exchanger 1 in neonatal mouse cardiomyocytes. These results raise exciting new questions regarding potentially dynamic roles for ankyrin proteins in the biogenesis and maintenance of specialized membrane domains in excitable cells.

Received for publication, July 26, 2006 , and in revised form, December 1, 2006.

^* This work was supported by National Institutes of Health Grants R01HL084583 and R01HL083422. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S3.

¹ Supported by the Postdoctoral Training Program in Neurogenomics (T32 MH065215).

² To whom correspondence should be addressed: Dept. of Internal Medicine, University of Iowa Carver College of Medicine, 285 Newton Rd; CBRB 2283, IA City, IA 52242. Tel.: 319-335-9691; Fax: 319-353-5552; E-mail: peter-mohler{at}uiowa.edu.

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