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Departments of Neurology and Applied Physiology, University of Ulm, Ulm, Germany (T.V.W., S.B., S.M., H.L.); and Department of Physiology, University of Tübingen, Tübingen, Germany (G.S.)
Retigabine (RTG) is an anticonvulsant drug with a novel mechanism of action. It activates neuronal KCNQ-type K+ channels by inducing a large hyperpolarizing shift of steady-state activation. To identify the structural determinants of KCNQ channel activation by RTG, we constructed a set of chimeras using the neuronal Kv7.2 (KCNQ2) channel, which is activated by RTG, and the cardiac Kv7.1 (KCNQ1) channel, which is not affected by this drug. Substitution of either the S5 or the S6 segment in Kv7.2 by the respective parts of Kv7.1 led to a complete loss of activation by RTG. Trp236 in the cytoplasmic part of S5 and the conserved Gly301 in S6 (Kv7.2), considered as the gating hinge (Ala336 in Kv7.1), were found to be crucial for the RTG effect: mutation of these residues could either knockout the effect in Kv7.2 or restore it partially in Kv7.1/Kv7.2 chimeras. We propose that RTG binds to a hydrophobic pocket formed upon channel opening between the cytoplasmic parts of S5 and S6 involving Trp236 and the channel's gate, which could well explain the strong shift in voltage-dependent activation.
Address correspondence to: Dr. Holger Lerche, Neurologische Klinik/Abteilung Angewandte Physiologie, Universität Ulm, Zentrum Klinische Forschung, Helmholtzstr. 8/1, 89081 Ulm, Germany. E-mail: holger.lerche{at}medizin.uni-ulm.de
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