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J. Biol. Chem. 281 (22): 15194-15200

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Modulation of Voltage-dependent Shaker Family Potassium Channels by an Aldo-Keto Reductase*{diamondsuit}

Jun Weng1, Yu Cao1, Noah Moss, , and Ming Zhou2

Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Abstract: The beta subunit (Kvbeta) of the Shaker family voltage-dependent potassium channels (Kv1) is a cytosolic protein that forms a permanent complex with the channel. Sequence and structural conservation indicates that Kvbeta resembles an aldo-keto reductase (AKR), an enzyme that catalyzes a redox reaction using an NADPH cofactor. A putative AKR in complex with a Kv channel has led to the hypothesis that intracellular redox potential may dynamically influence the excitability of a cell through Kvbeta. Since the AKR function of Kvbeta has never been demonstrated, a direct functional coupling between the two has not been established. We report here the identification of Kvbeta substrates and the demonstration that Kvbeta is a functional AKR. We have also found that channel function is modulated when the Kvbeta-bound NADPH is oxidized. Further studies of the enzymatic properties of Kvbeta seem to favor the role of Kvbeta as a redox sensor. These results suggest that Kvbeta may couple the excitability of the cell to its metabolic state and present a new avenue of research that may lead to understanding of the physiological functions of Kvbeta.

Received for publication December 27, 2005. Revision received March 23, 2006.

* This work was supported by the National Multiple Sclerosis Society Pilot Research Award, the March of Dimes Birth Defects Foundation Research Grant 5-FY06-20, the American Heart Association Grant SDG 0630148N, and the National Institutes of Health Grant HL086392 (all to M. Z.). 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.

{diamondsuit} This article was selected as a Paper of the Week.

1 These authors contributed equally to this work.

2 To whom correspondence should be addressed: Ming Zhou, Dept. of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, 630 West 168th St., New York, NY 10032. Tel.: 212-342-3722; Fax: 212-305-5775; E-mail: mz2140{at}

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