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Differential Roles of S6 Domain Hinges in the Gating of KCNQ Potassium Channels

Guiscard Seebohm ^*, Nathalie Strutz-Seebohm ^*, Oana N. Ureche ^*, Ravshan Baltaev ^*, Angelika Lampert ^* , Ganna Kornichuk ^*, Kaichiro Kamiya , Thomas V. Wuttke , Holger Lerche , Michael C. Sanguinetti ^¶ and Florian Lang ^*

^* Physiologisches Institut I, Universität Tübingen, D-72076 Tübingen, Germany; Department of Neurology, Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut; Department of Circulation, Nagoya, Japan; Departments of Applied Physiology and Neurology, University of Ulm, D-89081 Ulm, Germany; and ^¶ Department of Physiology and Nora Eccles Harrison Cardiovascular Research & Training Institute, University of Utah, Salt Lake City, Utah

Correspondence: Address reprint requests to Guiscard Seebohm, PhD, Physiologisches Institut 1, Universität Tübingen, Gmelinstr. 5, D-72076 Tübingen, Germany. Tel.: 49-7071-2972194; Fax: 49-7071-295618; E-mail: guiscard.seebohm{at}gmx.de.

Voltage-gated K⁺ channel activation is proposed to result from simultaneous bending of all S6 segments away from the central axis, enlarging the aperture of the pore sufficiently to permit diffusion of K⁺ into the water-filled central cavity. The hinge position for the bending motion of each S6 segment is proposed to be a Gly residue and/or a Pro-Val-Pro motif in Kv1–Kv4 channels. The KCNQ1 (Kv7.1) channel has Ala-336 in the Gly-hinge position and Pro-Ala-Gly. Here we show that mutation of Ala-336 to Gly in KCNQ1 increased current amplitude and shifted the voltage dependence of activation to more negative potentials, consistent with facilitation of hinge activity that favors the open state. In contrast, mutation of Ala-336 to Cys or Thr shifted the voltage dependence of activation to more positive potentials and reduced current amplitude. Mutation of the putative Gly hinge to Ala in KCNQ2 (Kv7.2) abolished channel function. Mutation-dependent changes in current amplitude, but not kinetics, were found in heteromeric KCNQ1/KCNE1 channels. Mutation of the Pro or Gly of the Pro-Ala-Gly motif to Ala abolished KCNQ1 function and introduction of Gly in front of the Ala-mutations partially recovered channel function, suggesting that flexibility at the PAG is important for channel activation.

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