Retigabine: Bending Potassium Channels to Our Will

The New Anticonvulsant Retigabine Favors Voltage-dependent Opening of the Kv7.2 (KCNQ2) Channel by Binding to Its Activation Gate Wuttke TV, Seebohm G, Bail S, Maljevic S, Lerche H Mol Pharmacol 2005;67:1009–1017 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 by using the neuronal K V 7.2 ( KCNQ2) channel, which is activated by RTG, and the cardiac K V 7.1 ( KCNQ1) channel, which is not affected by this drug. Substitution of either the S5 or the S6 segment in K V 7.2 by the respective parts of K V 7.1 led to a complete loss of activation by RTG. Trp236 in the cytoplasmic part of S5 and the conserved Gly301 in S6 (K V 7.2), considered as the gating hinge (Ala336 in K V 7.1), were found to be crucial for the RTG effect: mutation of these residues could either knock out the effect in K V 7.2 or restore it partially in K V 7.1/K V 7.2 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.