Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation

doi:10.1007/s00424-013-1345-6

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 神经药理学研究国际科学家工作站

	Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation
	Wan, Xia 1,2,6; Lu, Yungang 3; Chen, Xueqin 2; Xiong, Jian 2,3; Zhou, Yuanda 6; Li, Ping 2; Xia, Bingqing 2; Li, Min 2,4,5; Zhu, Michael X.2,3; Gao, Zhaobing2
刊名	PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
	2014-07
卷号	466 期号:7 页码:1273-1287
关键词	TRPA1 Voltage dependence Pore helix rotation Gating
ISSN号	0031-6768
DOI	10.1007/s00424-013-1345-6
文献子类	Article
英文摘要	Transient receptor potential A1 (TRPA1) is implicated in somatosensory processing and pathological pain sensation. Although not strictly voltage-gated, ionic currents of TRPA1 typically rectify outwardly, indicating channel activation at depolarized membrane potentials. However, some reports also showed TRPA1 inactivation at high positive potentials, implicating voltage-dependent inactivation. Here we report a conserved leucine residue, L906, in the putative pore helix, which strongly impacts the voltage dependency of TRPA1. Mutation of the leucine to cysteine (L906C) converted the channel from outward to inward rectification independent of divalent cations and irrespective to stimulation by allyl isothiocyanate. The mutant, but not the wild-type channel, displayed exclusively voltage-dependent inactivation at positive potentials. The L906C mutation also exhibited reduced sensitivity to inhibition by TRPA1 blockers, HC030031 and ruthenium red. Further mutagenesis of the leucine to all natural amino acids individually revealed that most substitutions at L906 (15/19) resulted in inward rectification, with exceptions of three amino acids that dramatically reduced channel activity and one, methionine, which mimicked the wild-type channel. Our data are plausibly explained by a bimodal gating model involving both voltage-dependent activation and inactivation of TRPA1. We propose that the key pore helix residue, L906, plays an essential role in responding to the voltage-dependent gating.
资助项目	National Key Basic Research Program of China[2013CB910604] ; National Science and Technology Major Project on "Key New Drug Creation and Manufacturing Program"[2013ZX09103001-016] ; National Natural Science Foundation of China Grant for Excellent Key Laboratory[81123004] ; Special Research Foundation of Chinese Academy of Sciences[F030304:61327014] ; US National Institutes of Health[R01DK081654] ; US National Institutes of Health[U54MH084691]
WOS关键词	POTENTIAL CHANNEL TRPA1 ; POTASSIUM CHANNELS ; K+ CHANNELS ; MOLECULAR DETERMINANTS ; COVALENT MODIFICATION ; INWARD RECTIFICATION ; SELECTIVITY FILTER ; DIRECT ACTIVATION ; XENOPUS-OOCYTES ; CALCIUM-IONS
WOS研究方向	Physiology
语种	英语
出版者	SPRINGER
WOS记录号	WOS:000338224700004
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/277010]
专题	神经药理学研究国际科学家工作站成果转移转化处
通讯作者	Zhou, Yuanda
作者单位	1.Nanchuan Dist Peoples Hosp, Dept Pharm, Chongqing, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 200031, Peoples R China; 3.Univ Texas Hlth Sci Ctr Houston, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USA; 4.Johns Hopkins Univ, Solomon H Snyder Dept Neurosci, High Throughput Biol Ctr, Baltimore, MD USA; 5.Johns Hopkins Univ, Sch Med, Johns Hopkins Ion Channel Ctr, Baltimore, MD USA 6.Chongqing Med Univ, Dept Clin Pharmacol, Affiliated Hosp 1, Chongqing, Peoples R China;
推荐引用方式 GB/T 7714	Wan, Xia,Lu, Yungang,Chen, Xueqin,et al. Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation[J]. PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY,2014,466(7):1273-1287.
APA	Wan, Xia.,Lu, Yungang.,Chen, Xueqin.,Xiong, Jian.,Zhou, Yuanda.,...&Gao, Zhaobing.(2014).Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation.PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY,466(7),1273-1287.
MLA	Wan, Xia,et al."Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation".PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY 466.7(2014):1273-1287.