title: The Sensorless Pore Module of Voltage-gated K+ Channel Family 7 Embodies the Target Site for the Anticonvulsant Retigabine.
abstract: KCNQ (voltage-gated K(+) channel family 7 (Kv7)) channels control cellular excitability and underlie the K(+) current sensitive to muscarinic receptor signaling (the M current) in sympathetic neurons. Here we show that the novel anti-epileptic drug retigabine (RTG) modulates channel function of pore-only modules (PMs) of the human Kv7.2 and Kv7.3 homomeric channels and of Kv7.2/3 heteromeric channels by prolonging the residence time in the open state. In addition, the Kv7 channel PMs are shown to recapitulate the single-channel permeation and pharmacological specificity characteristics of the corresponding full-length proteins in their native cellular context. A mutation (W265L) in the reconstituted Kv7.3 PM renders the channel insensitive to RTG and favors the conductive conformation of the PM, in agreement to what is observed when the Kv7.3 mutant is heterologously expressed. On the basis of the new findings and homology models of the closed and open conformations of the Kv7.3 PM, we propose a structural mechanism for the gating of the Kv7.3 PM and for the site of action of RTG as a Kv7.2/Kv7.3 K(+) current activator. The results validate the modular design of human Kv channels and highlight the PM as a high-fidelity target for drug screening of Kv channels.
authors.affiliation: From the Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, California 92093.
authors.forename: Ruhma
authors.initials: R
authors.lastname: Syeda
authors.affiliation: From the Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, California 92093.
authors.forename: Jose S
authors.initials: JS
authors.lastname: Santos
authors.affiliation: From the Section of Neurobiology, Division of Biological Sciences, University of California San Diego, La Jolla, California 92093 mmontal@ucsd.edu.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Montal
mesh_terms: D019943:Amino Acid Substitution; D000927:Anticonvulsants / Q000737:chemistry* / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D051658:KCNQ2 Potassium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051659:KCNQ3 Potassium Channel / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D020125:Mutation, Missense; D010655:Phenylenediamines / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D051659:KCNQ3 Potassium Channel; D010655:Phenylenediamines; C101866:ezogabine
keywords: KCNQ; Kv7; KvLm; channel activation; epilepsy; gating; ion channel; pore module; potassium channel; retigabine