Retigabine is a novel anticonvulsant compound now in clinical phase II development. It has previously been shown to enhance currents generated by KCNQ2/3 K+ channels (Main et al. 2000; Wickenden et al. 2000), which are considered to be molecular correlates of some mammalian neuronal M channels (Wang et al. 1998). In the present study, we have characterised the actions of retigabine on currents generated by these and other members of the KCNQ family and on the native M current in rat sympathetic neurons.
KCNQ currents were recorded from CHO cells expressing homomeric KCNQ1, -2, -3 or -4 channels or heteromeric KCNQ2/3 channels, as described by Selyanko et al. (2000). Retigabine (10 µM) increased current amplitudes in cells expressing KCNQ2, -3, -4 and -2/3 channels and shifted the voltage dependence of channel activation. Maximum shifts (mV) were: KCNQ2, -24.2; KCNQ3, -42.8; KCNQ4, -24.6; KCNQ2/3, -30.4. EC50 values for half-maximal shifts (µM; mean ± S.E.M. (n)) were: KCNQ2, 2.5 ± 0.6 (5); KCNQ3, 0.6 ± 0.3 (3); KCNQ4, 5.2 ± 0.9 (3); KCNQ2/3, 1.9 ± 0.2 (5). In contrast, retigabine did not enhance cardiac KCNQ1 currents but instead, at high concentrations (100 µM), reduced currents recorded at strongly positive potentials.
Retigabine also enhanced native M-type currents recorded from neurones dissociated from superior cervical sympathetic ganglia excised from humanely killed rats (see Selyanko et al. 1992). At 10 µM, retigabine produced a 21 mV left-shift in the activation curve for the linopirdine-sensitive component of outward current. In unclamped neurons, retigabine produced a hyper-polarisation and reduced the number of action potentials produced by depolarising current injections, without change in action potential configuration. If replicated in central neurones, this could account for retigabine’s anti-epileptic action.This work was supported by the UK Medical Research Council, The Wellcome Trust and Glaxo SmithKline, UK. We thank Dr D. Trezise and Dr M. Main (Glaxo SmithKline, Stevenage, UK) for retigabine and for helpful discussions, Dr D. KcKinnon for hKCNQ2 and rKCNQ3 cDNAs, Dr M. Keating for hKCNQ1 and Dr T. Jentsch for KCNQ4. We are also grateful to Dr A. Selyanko for all his suggestions and discussions.
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