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Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels

文献类型：期刊论文

作者Zhou, Pingzheng2; Yu, Haibo1,4; Gu, Min3; Nan, Fa-jun3; Gao, Zhaobing2; Li, Min1,2,4
刊名PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
出版日期2013-05-21
卷号110期号:21页码:8726-8731
关键词gating modifier pain cardiac arrhythmias hyperexcitability chemical probe
ISSN号0027-8424
DOI10.1073/pnas.1302167110
文献子类Article
英文摘要Pharmacological augmentation of neuronal KCNQ muscarinic (M) currents by drugs such as retigabine (RTG) represents a first-in-class therapeutic to treat certain hyperexcitatory diseases by dampening neuronal firing. Whereas all five potassium channel subtypes (KCNQ1-KCNQ5) are found in the nervous system, KCNQ2 and KCNQ3 are the primary players that mediate M currents. We investigated the plasticity of subtype selectivity by two M current effective drugs, retigabine and zinc pyrithione (ZnPy). Retigabine is more effective on KCNQ3 than KCNQ2, whereas ZnPy is more effective on KCNQ2 with no detectable effect on KCNQ3. In neurons, activation of muscarinic receptor signaling desensitizes effects by retigabine but not ZnPy. Importantly, reduction of phosphatidylinositol 4,5-bisphosphate (PIP2) causes KCNQ3 to become sensitive to ZnPy but lose sensitivity to retigabine. The dynamic shift of pharmacological selectivity caused by PIP2 may be induced orthogonally by voltage-sensitive phosphatase, or conversely, abolished by mutating a PIP2 site within the S4-S5 linker of KCNQ3. Therefore, whereas drug-channel binding is a prerequisite, the drug selectivity on M current is dynamic and may be regulated by receptor signaling pathways via PIP2.
WOS关键词VOLTAGE-SENSOR ; ANTICONVULSANT RETIGABINE ; K+ CHANNELS ; MOLECULAR DETERMINANTS ; ACTIVATION ; OPENER ; PIP2 ; PHOSPHOINOSITIDES ; EZOGABINE ; BINDING
资助项目National Key Basic Research Program of China[2013CB910604] ; National Institutes of Health[U54MH084691] ; National Institutes of Health[1R03MH090837-01]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000320328700087
出版者NATL ACAD SCIENCES
源URL[http://119.78.100.183/handle/2S10ELR8/277613]  
专题神经药理学研究国际科学家工作站
中科院受体结构与功能重点实验室
新药研究国家重点实验室
通讯作者Li, Min
作者单位1.Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, Chinese Natl Drug Screening Ctr, Shanghai 201203, Peoples R China;
4.Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA;
推荐引用方式
GB/T 7714		 Zhou, Pingzheng,Yu, Haibo,Gu, Min,et al. Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2013,110(21):8726-8731.
APA Zhou, Pingzheng,Yu, Haibo,Gu, Min,Nan, Fa-jun,Gao, Zhaobing,&Li, Min.(2013).Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels.PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,110(21),8726-8731.
MLA Zhou, Pingzheng,et al."Phosphatidylinositol 4,5-bisphosphate alters pharmacological selectivity for epilepsy-causing KCNQ potassium channels".PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110.21(2013):8726-8731.

入库方式： OAI收割

来源：上海药物研究所

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