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J. Biol. Chem., Vol. 283, Issue 7, 3702-3707, February 15, 2008

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Endoplasmic Reticulum Retention and Rescue by Heteromeric Assembly Regulate Human ERG 1a/1b Surface Channel Composition^*

Pallavi Phartiyal, Harinath Sale, Eugenia M. C. Jones, and Gail A. Robertson¹

From the Department of Physiology and the Cellular and Molecular Biology Program, University of Wisconsin, Madison, Wisconsin 53711

Defects in the trafficking of subunits encoded by the human ether-à-go-go-related gene (hERG1) can lead to catastrophic arrhythmias and sudden cardiac death due to a reduction in I_Kr-mediated repolarization. Native I_Kr channels are composed of two subunits, hERG 1a and 1b. In heterologous expression systems, hERG 1b subunits efficiently produce current only in heteromeric combination with hERG 1a. We used Western blot analysis and electrophysiological recordings in HEK-293 cells and Xenopus oocytes to monitor hERG 1b maturation in the secretory pathway and to determine the factors regulating surface expression of hERG 1b subunits. We found that 1b subunits expressed alone were largely retained in the endoplasmic reticulum (ER), thus accounting for the poor functional expression of homomeric 1b currents. Association with hERG 1a facilitated 1b ER export and surface expression. We show that hERG 1b subunits fail to mature because of an "RXR" ER retention signal specific to the 1b N terminus of the human sequence and not conserved in other species. Mutating the RXR facilitated maturation and functional expression of homomeric hERG 1b channels in a charge-dependent manner. Co-expression of the 1b RXR mutants with hERG 1a did not further enhance 1b maturation, suggesting that hERG 1a promotes 1b trafficking by overcoming the RXR-mediated retention. Thus, selective trafficking mechanisms regulate subunit composition of surface hERG channels.

Received for publication, November 1, 2007 , and in revised form, November 28, 2007.

^* This work was supported by National Institutes of Health Grant R01HL081780 (to G. A. R.) and an American Heart Association predoctoral fellowship (to P. P.). 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 To whom correspondence should be addressed: Dept. of Physiology, University of Wisconsin Satellite Laboratories, 601 Science Dr., Madison, WI 53711. Tel.: 608-265-3339; Fax: 608-265-7821; E-mail: robertson{at}physiology.wisc.edu.

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