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J Gen Physiol. 2018 Oct 1;150(10):1421-1431. doi: 10.1085/jgp.201812013. Epub 2018 Aug 30.

One drug-sensitive subunit is sufficient for a near-maximal retigabine effect in KCNQ channels.

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Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
Department of Drug Design and Pharmacology (Center for Biopharmaceuticals), University of Copenhagen, Copenhagen, Denmark.
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada


Retigabine is an antiepileptic drug and the first voltage-gated potassium (Kv) channel opener to be approved for human therapeutic use. Retigabine is thought to interact with a conserved Trp side chain in the pore of KCNQ2-5 (Kv7.2-7.5) channels, causing a pronounced hyperpolarizing shift in the voltage dependence of activation. In this study, we investigate the functional stoichiometry of retigabine actions by manipulating the number of retigabine-sensitive subunits in concatenated KCNQ3 channel tetramers. We demonstrate that intermediate retigabine concentrations cause channels to exhibit biphasic conductance-voltage relationships rather than progressive concentration-dependent shifts. This suggests that retigabine can exert its effects in a nearly "all-or-none" manner, such that channels exhibit either fully shifted or unshifted behavior. Supporting this notion, concatenated channels containing only a single retigabine-sensitive subunit exhibit a nearly maximal retigabine effect. Also, rapid solution exchange experiments reveal delayed kinetics during channel closure, as retigabine dissociates from channels with multiple drug-sensitive subunits. Collectively, these data suggest that a single retigabine-sensitive subunit can generate a large shift of the KCNQ3 conductance-voltage relationship. In a companion study (Wang et al. 2018. J. Gen. Physiol., we contrast these findings with the stoichiometry of a voltage sensor-targeted KCNQ channel opener (ICA-069673), which requires four drug-sensitive subunits for maximal effect.

[Available on 2019-04-01]
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