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J. Biol. Chem., Vol. 283, Issue 11, 6968-6978, March 14, 2008

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Identification of a New Co-factor, MOG1, Required for the Full Function of Cardiac Sodium Channel Na_v1.5^*

Ling Wu¹, Sandro L. Yong¹, Chun Fan, Ying Ni, Shin Yoo, Teng Zhang, Xianqin Zhang, Carlos A. Obejero-Paz^¶, Hyun-Jin Rho, Tie Ke, Przemyslaw Szafranski^||, Stephen W. Jones^¶, Qiuyun Chen, and Qing Kenneth Wang^**2

From the Department of Molecular Cardiology, Lerner Research Institute, Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Tausig Cancer Center, Cleveland Clinic, Cleveland, Ohio 44195, the Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio 44115, the ^¶Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, ^||Department of Pathology, Baylor College of Medicine, Houston, Texas 77030, the ^**Department of Chemistry, Cleveland State University, Cleveland, Ohio 44115, Key Laboratory of Molecular Biophysics of Ministry of Education and Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan 430074, China

The cardiac sodium channel Na_v1.5 is essential for the physiological function of the heart and contributes to lethal cardiac arrhythmias and sudden death when mutated. Here, we report that MOG1, a small protein that is highly conserved from yeast to humans, is a central component of the channel complex and modulates the physiological function of Na_v1.5. The yeast two-hybrid screen identified MOG1 as a new protein that interacts with the cytoplasmic loop II (between transmembrane domains DII and DIII) of Na_v1.5. The interaction was further demonstrated by both in vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation assays in both HEK293 cells with co-expression of MOG1 and Na_v1.5 and native cardiac cells. Co-expression of MOG1 with Na_v1.5 in HEK293 cells increased sodium current densities. In neonatal myocytes, overexpression of MOG1 increased current densities nearly 2-fold. Western blot analysis revealed that MOG1 increased cell surface expression of Na_v1.5, which may be the underlying mechanism by which MOG1 increased sodium current densities. Immunostaining revealed that in the heart, MOG1 was expressed in both atrial and ventricular tissues with predominant localization at the intercalated discs. In cardiomyocytes, MOG1 is mostly localized in the cell membrane and co-localized with Na_v1.5. These results indicate that MOG1 is a critical regulator of sodium channel function in the heart and reveal a new cellular function for MOG1. This study further demonstrates the functional diversity of Na_v1.5-binding proteins, which serve important functions for Na_v1.5 under different cellular conditions.

Received for publication, November 28, 2007 , and in revised form, December 26, 2007.

^* This work was supported by NHLBI, National Institutes of Health, Grants R01 HL66251 (to Q. K. W.), the China National Basic Research Program (973 Program 2007CB512000 and 2007CB512002) (to Q. K. W.), American Heart Association Established Investigator Award 0440157N (to Q. K. W.), and an American Heart Association Scientist Development Grant 0630193N (to Q. C.). 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.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Center for Cardiovascular Genetics/NE40, The Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195. Tel.: 216-445-0570; Fax: 216-636-1231; E-mail: wangq2{at}ccf.org.

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