Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers.
Noninactivating potassium current formed by KCNQ2 (Kv7.2) and KCNQ3 (Kv7.3) subunits resembles neuronal M-currents which are activated by voltage and play a critical role in controlling membrane excitability. Activation of voltage-gated potassium channels by a chemical opener is uncommon. Therefore, the mechanisms of action are worthy further investigation. Retigabine and zinc pyrithione are two activators for KCNQ channels but their molecular interactions with KCNQ channel remain largely elusive. Here we report that retigabine and zinc pyrithione recognize two different sites of KCNQ2 channels. Their agonistic actions are noncompetitive and allow for simultaneous binding of two different activators on the same channel complex, hence giving rise to combinatorial potentiation with characteristic properties of both openers. Examining their effects on mutant channels, we showed zinc pyrithione is capable of opening nonconductive channels and coapplication of zinc pyrithione and retigabine could restore a disease mutant channel similar to wild type. Our results indicate two independent activator binding sites present in KCNQ channels. The resultant combinatorial potentiation by multiple synthetic chemical openers indicates that KCNQ channels are accessible to various types and combinations of pharmacological regulation.
Xiong
Qiaojie
Q
Departments of Neuroscience, Physiology and High Throughput Biology Center, School of Medicine, Johns Hopkins University, 733 North Broadway, Baltimore, MD 21205, USA.
Sun
Haiyan
H
Zhang
Yangming
Y
Nan
Fajun
F
Li
Min
M
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D016466:CHO Cells; D002219:Carbamates / Q000378:metabolism* / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004594:Electrophysiology; D051656:KCNQ Potassium Channels / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D016296:Mutagenesis; D009942:Organometallic Compounds / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010655:Phenylenediamines / Q000378:metabolism* / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics; D011725:Pyridines / Q000378:metabolism* / Q000494:pharmacology; D017422:Sequence Analysis, DNA
D002219:Carbamates; D051656:KCNQ Potassium Channels; D009942:Organometallic Compounds; D010655:Phenylenediamines; D011725:Pyridines; C101866:ezogabine; C010423:pyrithione zinc