Isoform-specific prolongation of Kv7 (KCNQ) potassium channel opening mediated by new molecular determinants for drug-channel interactions.
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.
Gao
Zhaobing
Z
Department of Neuroscience, High Throughput Biology Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Zhang
Tangzhi
T
Wu
Meng
M
Xiong
Qiaojie
Q
Sun
Haiyan
H
Zhang
Yinan
Y
Zu
Liansuo
L
Wang
Wei
W
Li
Min
M
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
D001549:Benzamides; D051656:KCNQ Potassium Channels; D004364:Pharmaceutical Preparations; D020033:Protein Isoforms