Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites.
Polyunsaturated fatty acids inhibit a pentameric ligand-gated ion channel through one of two binding sites.
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DOI：
10.7554/elife.74306
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发表时间：
2022-01-04
期刊：
影响因子：
7.7
通讯作者：
Cheng WW
中科院分区：
文献类型：
--
作者：
Dietzen NM;Arcario MJ;Chen LJ;Petroff JT 2nd;Moreland KT;Krishnan K;Brannigan G;Covey DF;Cheng WW
多不饱和脂肪酸（PUFAs）可抑制五聚体配体门控离子通道（plgic），但其抑制机制尚不清楚。PUFA，二十二碳六烯酸（DHA），比棕榈酸更有效地抑制pLGIC， ELIC的激动剂反应，类似于在GABAA受体和烟碱乙酰胆碱受体中观察到的效果。利用光亲和标记和粗粒度的分子动力学模拟，我们确定了ELIC外跨膜结构域（TMD）中的两个脂肪酸结合位点。脂肪酸与光标记位点的结合对DHA比棕榈酸具有选择性，并且对激动剂结合状态具有特异性。外TMD中两个脂肪酸结合位点之一的十六烷基甲乙硫磺酸修饰再现了PUFAs对ELIC的抑制作用。结果表明，DHA选择性结合ELIC外TMD的多个位点，但与单个亚基内位点的状态依赖性结合介导了DHA对ELIC的抑制。
Polyunsaturated fatty acids (PUFAs) inhibit pentameric ligand-gated ion channels (pLGICs) but the mechanism of inhibition is not well understood. The PUFA, docosahexaenoic acid (DHA), inhibits agonist responses of the pLGIC, ELIC, more effectively than palmitic acid, similar to the effects observed in the GABAA receptor and nicotinic acetylcholine receptor. Using photo-affinity labeling and coarse-grained molecular dynamics simulations, we identified two fatty acid binding sites in the outer transmembrane domain (TMD) of ELIC. Fatty acid binding to the photolabeled sites is selective for DHA over palmitic acid, and specific for an agonist-bound state. Hexadecyl-methanethiosulfonate modification of one of the two fatty acid binding sites in the outer TMD recapitulates the inhibitory effect of PUFAs in ELIC. The results demonstrate that DHA selectively binds to multiple sites in the outer TMD of ELIC, but that state-dependent binding to a single intrasubunit site mediates DHA inhibition of ELIC.
DOI：
10.1085/jgp.200709764
发表时间：
2007-09
期刊：
The Journal of general physiology
影响因子：
--
作者：
Enkvetchakul D;Jeliazkova I;Bhattacharyya J;Nichols CG
通讯作者：
Nichols CG