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

The Journal of General Physiology
Michael C YauHarley T Kurata

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 ...Continue Reading

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Citations

Oct 31, 2018·The Journal of General Physiology·Caroline K WangHarley T Kurata
Jul 12, 2020·Epilepsia·Richard KanyoHarley T Kurata
Sep 1, 2018·The Journal of General Physiology·Alice W WangHarley T Kurata
Jul 9, 2020·Frontiers in Pharmacology·Carlos A Villalba-Galea
May 8, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Fan ZhangKeWei Wang
Oct 22, 2019·Assay and Drug Development Technologies·Benjamin WilenkinBirgit T Priest

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BETA
electrophoresis
transfection

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pClamp

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