Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers

doi:10.1073/pnas.0712256105

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	Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers
	Xiong, Qiaojie 1,2; Sun, Haiyan 1,2; Zhang, Yangming3 ; Nan, Fajun3 ; Li, Min 1,2
刊名	PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
	2008-02-26
卷号	105 期号:8 页码:3128-3133
关键词	channel opener epilepsy genetic mutants
ISSN号	0027-8424
DOI	10.1073/pnas.0712256105
文献子类	Article
英文摘要	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.
资助项目	NIGMS NIH HHS[GM078579] ; NIGMS NIH HHS[R01 GM070959] ; NIGMS NIH HHS[R01 GM078579] ; NIGMS NIH HHS[GM070959]
WOS关键词	CYSTEINE-MODIFYING REAGENT ; KCNQ2/KCNQ3 K+ CHANNELS ; ANTICONVULSANT RETIGABINE ; ACTIVATION ; EPILEPSY ; CELLS ; SUBUNITS ; D-23129 ; BRAIN ; BMS-204352
WOS研究方向	Science & Technology - Other Topics
语种	英语
出版者	NATL ACAD SCIENCES
WOS记录号	WOS:000253567900068
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/272974]
专题	神经药理学研究国际科学家工作站国家新药筛选中心
通讯作者	Li, Min
作者单位	1.Johns Hopkins Univ, Sch Med, Dept Neurosci, Dept Physiol, Baltimore, MD 21205 USA; 2.Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA; 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Xiong, Qiaojie,Sun, Haiyan,Zhang, Yangming,et al. Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2008,105(8):3128-3133.
APA	Xiong, Qiaojie,Sun, Haiyan,Zhang, Yangming,Nan, Fajun,&Li, Min.(2008).Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,105(8),3128-3133.
MLA	Xiong, Qiaojie,et al."Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 105.8(2008):3128-3133.