Retigabine (RTG) is a novel anticonvulsant drug which activates neuronal KCNQ-type K⁺ channels (K_v7.2–5) by shifting voltage-dependent activation in the hyperpolarizing direction. The structural determinants of KCNQ channel activation by RTG have been recently identified by using chimeras constructed of the RTG-sensitive neuronal K_v7.2 (KCNQ2) or K_v7.3 (KCNQ3) channels on one, and of the RTG-insensitive cardiac K_v7.1 (KCNQ1) channel on the other hand. It could be shown that amino acids crucial for the RTG effect are located in the cytoplasmic pore region containing the activation gate of voltage-gated K channels. In particular, mutation of a single tryptophane residue in S5 (Trp-236 in K_v7.2) knocked out the RTG effect in K_v7.2–5. Introduction of the conserved Gly-301 in S6 (K_v7.2), considered as the gating hinge (Ala-336 in K_v7.1) led to a recovery of the RTG-induced shift in K_v7.1/K_v7.2 chimeras. These data suggest that RTG could bind to a hydrophobic pocket formed upon channel opening between the cytoplasmic parts of S5 and S6 involving Trp-236 and the channel's gate, thereby stabilizing the open state of neuronal KCNQ channels.