The anticonvulsant retigabine targets the neuronal M-channel but has adverse clinical effects due to its poor K _(V)7 subtype specificity. Larsson et al. reveal that the selectivity of retigabine is improved by coapplication with the endocannabinoid arachidonoyl-L-serine. Retigabine is unique among anticonvulsant drugs by targeting the neuronal M-channel, which is composed of K _(V)7.2/K _(V)7.3 and contributes to the negative neuronal resting membrane potential. Unfortunately, retigabine causes adverse effects, which limits its clinical use. Adverse effects may be reduced by developing M-channel activators with improved K _(V)7 subtype selectivity. The aim of this study was to evaluate the prospect of endocannabinoids as M-channel activators, either in isolation or combined with retigabine. Human K _(V)7 channels were expressed in Xenopus laevis oocytes. The effect of extracellular application of compounds with different properties was studied using two-electrode voltage clamp electrophysiology. Site-directed mutagenesis was used to construct channels with mutated residues to aid in the mechanistic understanding of these effects. We find that arachidonoyl-L-serine (ARA-S), a weak endocannabinoid, potently activates the human M-channel expressed in Xenopus oocytes. Importantly, we show that ARA-S activates the M-channel via a different mechanism and displays a different K _(V)7 subtype selectivity compared with retigabine. We demonstrate that coapplication of ARA-S and retigabine at low concentrations retains the effect on the M-channel while limiting effects on other K _(V)7 subtypes. Our findings suggest that improved K _(V)7 subtype selectivity of M-channel activators can be achieved through strategically combining compounds with different subtype selectivity.
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