The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate.

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 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 knockout 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.