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One drug-sensitive subunit is sufficient for a near-maximal retigabine effect in KCNQ channels.
Yau, Michael C; Kim, Robin Y; Wang, Caroline K; Li, Jingru; Ammar, Tarek; Yang, Runying Y; Pless, Stephan A; Kurata, Harley T.
Afiliação
  • Yau MC; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • Kim RY; Department of Drug Design and Pharmacology (Center for Biopharmaceuticals), University of Copenhagen, Copenhagen, Denmark.
  • Wang CK; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • Li J; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • Ammar T; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • Yang RY; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • Pless SA; Department of Pharmacology, Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
  • Kurata HT; Department of Drug Design and Pharmacology (Center for Biopharmaceuticals), University of Copenhagen, Copenhagen, Denmark.
J Gen Physiol ; 150(10): 1421-1431, 2018 10 01.
Article em En | MEDLINE | ID: mdl-30166314
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilenodiaminas / Carbamatos / Canal de Potássio KCNQ3 / Anticonvulsivantes Tipo de estudo: Diagnostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fenilenodiaminas / Carbamatos / Canal de Potássio KCNQ3 / Anticonvulsivantes Tipo de estudo: Diagnostic_studies Limite: Animals Idioma: En Ano de publicação: 2018 Tipo de documento: Article