Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation.
Bimodal voltage dependence of TRPA1: mutations of a key pore helix residue reveal strong intrinsic voltage-dependent inactivation.
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TRPA1 的双峰电压依赖性：关键孔螺旋残基的突变揭示了强烈的内在电压依赖性失活
DOI：
10.1007/s00424-013-1345-6
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发表时间：
2014-07
影响因子：
4.5
通讯作者：
Gao, Zhaobing
中科院分区：
文献类型：
--
作者：
Wan, Xia;Lu, Yungang;Chen, Xueqin;Xiong, Jian;Zhou, Yuanda;Li, Ping;Xia, Bingqing;Li, Min;Zhu, Michael X.;Gao, Zhaobing
瞬时受体电位A1（TRPA 1）参与躯体感觉处理和病理性疼痛感觉。虽然不是严格的电压门控，TRPA 1的离子电流通常向外整流，表明通道激活去极化膜电位。然而，一些报告也显示TRPA 1在高正电位下失活，涉及电压依赖性失活。在这里，我们报告了一个保守的亮氨酸残基，L906，在推定的孔螺旋，强烈影响的电压依赖性的TRPA 1。亮氨酸突变为半胱氨酸（L906 C）转换通道从外向内向整流独立的二价阳离子和无关的烯丙基异硫氰酸酯的刺激。突变体，但不是野生型通道，显示完全电压依赖性失活在正电位。L906 C突变还表现出对TRPA 1阻断剂HC 030031和钌红抑制的敏感性降低。亮氨酸对所有天然氨基酸的进一步诱变分别揭示，在L906（15/19）处的大多数取代导致向内整流，除了显著降低通道活性的三个氨基酸和模拟野生型通道的甲硫氨酸之外。我们的数据是合理的解释双峰门控模型，涉及电压依赖性激活和失活的TRPA 1。我们建议，关键孔螺旋残基，L906，起着至关重要的作用，在响应电压依赖性门控。
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.
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DOI：
10.1523/jneurosci.5369-07.2008
发表时间：
2008-03-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andersson DA;Gentry C;Moss S;Bevan S
通讯作者：
Bevan S
影响因子：
3.3
作者：
Cavanaugh, E. J.;Simkin, D.;Kim, D.
通讯作者：
Kim, D.
影响因子：
4.5
作者：
Alpizar, Yeranddy A.;Gees, Maarten;Talavera, Karel
通讯作者：
Talavera, Karel
影响因子：
16.2
作者：
Kwan, KY;Allchorne, AJ;Corey, DP
通讯作者：
Corey, DP
DOI：
10.1016/j.bbamcr.2009.04.014
发表时间：
2009-07-01
影响因子：
5.1
作者：
Benedikt, Jan;Samad, Abdul;Vlachova, Viktorie
通讯作者：
Vlachova, Viktorie