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J. Biol. Chem., Vol. 282, Issue 18, 13637-13647, May 4, 2007

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Zn²⁺-dependent Redox Switch in the Intracellular T1-T1 Interface of a Kv Channel^*

Guangyu Wang¹, Candace Strang, Paul J. Pfaffinger, and Manuel Covarrubias²

From the Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 and the Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030

The thiol-based redox regulation of proteins plays a central role in cellular signaling. Here, we investigated the redox regulation at the Zn²⁺ binding site (HX₅CX₂₀CC) in the intracellular T1-T1 inter-subunit interface of a Kv4 channel. This site undergoes conformational changes coupled to voltage-dependent gating, which may be sensitive to oxidative stress. The main results show that internally applied nitric oxide (NO) inhibits channel activity profoundly. This inhibition is reversed by reduced glutathione and suppressed by intracellular Zn²⁺, and at least two Zn²⁺ site cysteines are required to observe the NO-induced inhibition (Cys-110 from one subunit and Cys-132 from the neighboring subunit). Biochemical evidence suggests strongly that NO induces a disulfide bridge between Cys-110 and Cys-132 in intact cells. Finally, further mutational studies suggest that intra-subunit Zn²⁺ coordination involving His-104, Cys-131, and Cys-132 protects against the formation of the inhibitory disulfide bond. We propose that the interfacial T1 Zn²⁺ site of Kv4 channels acts as a Zn²⁺-dependent redox switch that may regulate the activity of neuronal and cardiac A-type K⁺ currents under physiological and pathological conditions.

Received for publication, September 27, 2006 , and in revised form, January 29, 2007.

^* This work was supported by National Institutes of Health Research Grants R01 NS032337 (to M. C.), P01 NS037444 (to P. J. P.), and Training Grant T32 AA07463 (to G. W.). 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 and S2.

¹ To whom correspondence may be addressed: Dept. of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St., JAH241, Philadelphia, PA 19107. Tel.: 215-503-7883; Fax: 215-923-2218; E-mail: Guang-yu.Wang{at}jefferson.edu.

² To whom correspondence may be addressed: Dept. of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Thomas Jefferson University, 1020 Locust St., JAH245, Philadelphia, PA 19107. Tel.: 215-503-4341; Fax: 215-923-2218; E-mail: Manuel.Covarrubias{at}jefferson.edu.

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