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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.

Author information

1
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
2
Department of Drug Design and Pharmacology (Center for Biopharmaceuticals), University of Copenhagen, Copenhagen, Denmark.
3
Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada kurata@ualberta.ca.

Abstract

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. https://doi.org/10.1085/jgp.201812014), 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.

PMID:
30166314
PMCID:
PMC6168243
[Available on 2019-04-01]
DOI:
10.1085/jgp.201812013
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