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Vol. 58, Issue 2, 253-262, August 2000
Molecular Pharmacology, Neuroscience (J.R.B.D.) & Receptor
Chemistry (B.C.) Units, Glaxo-Wellcome Research & Development,
Stevenage, Hertfordshire, United Kingdom
Retigabine is a novel anticonvulsant with an unknown mechanism of
action. It 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 identified. In the present study we have
examined the effects of retigabine on recombinant human KCNQ2 and KCNQ3
potassium channels, expressed either alone or in combination in
Xenopus oocytes. Application of 10 µM retigabine to
oocytes expressing the KCNQ2/3 heteromeric channel shifted both the
activation threshold and voltage for half-activation by approximately
20 mV in the hyperpolarizing direction, leading to an increase in
current amplitude at test potentials between 
80 mV and +20 mV.
Retigabine also had a marked effect on KCNQ current kinetics,
increasing the rate of channel activation but slowing deactivation at a
given test potential. Similar effects of retigabine were observed in
oocytes expressing KCNQ2 alone, suggesting that KCNQ2 may be the
molecular target of retigabine. Membrane potential recordings in
oocytes expressing the KCNQ2/3 heteromeric channel showed that
application of retigabine leads to a concentration-dependent
hyperpolarization of the oocyte, from a resting potential of 63 mV
under control conditions to 85 mV in the presence of 100 µM
retigabine (IC50 = 5.2 µM). In control experiments
retigabine had no effect on either resting membrane potential or
endogenous oocyte membrane currents. In conclusion, we have shown that
retigabine acts as a KCNQ potassium channel opener. Because the
heteromeric KCNQ2/3 channel has recently been reported to underlie the
M-current, it is likely that M-current modulation can explain the
anticonvulsant actions of retigabine in animal models of epilepsy.
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