Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine

Retigabine is a novel anticonvulsant with an unknown mechanism of action. I t has recently been reported that retigabine modulates a potassium channel current in nerve growth factor-differentiated PC12 cells (Rundfeldt, 1999), however, to date the molecular correlate of this current has not been iden tified. In the present study we have examined the effects of retigabine on recombinant human KCNQ2 and KCNQ3 potassium channels, expressed either alon e or in combination in Xenopus oocytes. Application of 10 mu M retigabine t o oocytes expressing the KCNQ2/3 heteromeric channel shifted both the activ ation threshold and voltage for half-activation by approximately 20 mV in t he hyperpolarizing direction, leading to an increase in current amplitude a t test potentials between -80 mV and +20 mV. Retigabine also had a marked e ffect on KCNQ current kinetics, increasing the rate of channel activation b ut slowing deactivation at a given test potential. Similar effects of retig abine were observed in oocytes expressing KCNQ2 alone, suggesting that KCNQ 2 may be the molecular target of retigabine. Membrane potential recordings in oocytes expressing the KCNQ2/3 heteromeric channel showed that applicati on of retigabine leads to a concentration-dependent hyperpolarization of th e oocyte, from a resting potential of -63 mV under control conditions to -8 5 mV in the presence of 100 mu M retigabine (IC50 = 5.2 mu M). In control e xperiments retigabine had no effect on either resting membrane potential or endogenous oocyte membrane currents. In conclusion, we have shown that ret igabine acts as a KCNQ potassium channel opener. Because the heteromeric KC NQ2/3 channel has recently been reported to underlie the M-current, it is l ikely that M-current modulation can explain the anticonvulsant actions of r etigabine in animal models of epilepsy.