title: Isoform-specific prolongation of Kv7 (KCNQ) potassium channel opening mediated by new molecular determinants for drug-channel interactions.
abstract: Kv7 channels, especially Kv7.2 (KCNQ2) and Kv7.3 (KCNQ3), are key determinants for membrane excitability in the brain. Some chemical modulators of KCNQ channels are in development for use as anti-epileptic drugs, such as retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl)), which was recently approved for clinical use. In addition, several other compounds were also reported to potentiate activity of the Kv7 channels. It is therefore of interest to investigate compound-channel interactions, so that more insights may be gained to aid future development of therapeutics. We have conducted a screen of 20,000 compounds for KCNQ2 potentiators using rubidium flux combined with atomic absorption spectrometry. Here, we report the characterization of a series of new structures that display isoform specificity and induce a marked reduction of deactivation distinct from that of retigabine. Furthermore, KCNQ2(W236L), a previously reported mutation that abolishes sensitivity to retigabine, remains fully sensitive to these compounds. This result, together with mutagenesis and other studies, suggests that the reported compounds confer a unique mode of action and involve new molecular determinants on the channel protein, consistent with the idea of recognizing a new site on channel protein.
authors.affiliation: Department of Neuroscience, High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
authors.forename: Tangzhi
authors.initials: T
authors.lastname: Zhang
authors.forename: Meng
authors.initials: M
authors.lastname: Wu
authors.forename: Qiaojie
authors.initials: Q
authors.lastname: Xiong
authors.forename: Haiyan
authors.initials: H
authors.lastname: Sun
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liansuo
authors.initials: L
authors.lastname: Zu
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Min
authors.initials: M
authors.lastname: Li
mesh_terms: D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D015640:Ion Channel Gating / Q000187:drug effects*; D051656:KCNQ Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D001549:Benzamides; D051656:KCNQ Potassium Channels; D004364:Pharmaceutical Preparations; D020033:Protein Isoforms