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J. Biol. Chem., Vol. 283, Issue 33, 22649-22658, August 15, 2008

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Desensitization of Chemical Activation by Auxiliary Subunits

CONVERGENCE OF MOLECULAR DETERMINANTS CRITICAL FOR AUGMENTING KCNQ1 POTASSIUM CHANNELS^*

From the Department of Neuroscience and High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205

Chemical openers for KCNQ potassium channels are useful probes both for understanding channel gating and for developing therapeutics. The five KCNQ isoforms (KCNQ1 to KCNQ5, or Kv7.1 to Kv7.5) are differentially localized. Therefore, the molecular specificity of chemical openers is an important subject of investigation. Native KCNQ1 normally exists in complex with auxiliary subunits known as KCNE. In cardiac myocytes, the KCNQ1-KCNE1 (IsK or minK) channel is thought to underlie the I_Ks current, a component critical for membrane repolarization during cardiac action potential. Hence, the molecular and pharmacological differences between KCNQ1 and KCNQ1-KCNE1 channels have been important topics. Zinc pyrithione (ZnPy) is a newly identified KCNQ channel opener, which potently activates KCNQ2, KCNQ4, and KCNQ5. However, the ZnPy effects on cardiac KCNQ1 potassium channels remain largely unknown. Here we show that ZnPy effectively augments the KCNQ1 current, exhibiting an increase in current amplitude, reduction of inactivation, and slowing of both activation and deactivation. Some of these are reminiscent of effects by KCNE1. In addition, neither the heteromultimeric KCNQ1-KCNE1 channels nor native I_Ks current displayed any sensitivity to ZnPy, indicating that the static occupancy by a KCNE subunit desensitizes the reversible effects by a chemical opener. Site-directed mutagenesis of KCNQ1 reveals that residues critical for the potentiation effects by either ZnPy or KCNE are clustered together in the S6 region overlapping with the critical gating determinants. Thus, the convergence of potentiation effects and molecular determinants critical for both an auxiliary subunit and a chemical opener argue for a mechanistic overlap in causing potentiation.

Received for publication, March 28, 2008 , and in revised form, May 13, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM070959 and GM078579 (to M. L.). This work was also supported by a postdoctoral fellowship award from the American Heart Association (to Z. G.). 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 Neuroscience, Johns Hopkins University School of Medicine, BRB311, 733 N. Broadway, Baltimore, MD 21205. Fax: 410-614-1001; E-mail: minli{at}jhmi.edu.

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