NMR structures of the transmembrane domains of the 伪4尾2 nAChR

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• 作者：Vasyl Bondarenko^a ; David Mowrey^a ; ^c ; Tommy Tillman^a ; Tanxing Cui^a ; ^b ; Lu Tian Liu^a ; Yan Xu^a ; ^b ; ^d ; Pei Tang^a ; ^c ; ^d ; ^{tangp@upmc.edu}
• 关键词：Nicotinic acetylcholine receptor ; nAChR ; 伪4尾2 ; NMR ; Ion channel structure ; Cys-loop receptor
• 刊名：Biochimica et Biophysica Acta (BBA)/Biomembranes
• 出版年：2012
• 期刊代码：14_00052736
• 类别：bio
• 出版时间：May, 2012
• 卷：1818
• 期：5
• 页码：1261-1268
• 文件大小：1023 K

摘要

The 伪4尾2 nicotinic acetylcholine receptor (nAChR) is the predominant heteromeric subtype of nAChRs in the brain, which has been implicated in numerous neurological conditions. The structural information specifically for the 伪4尾2 and other neuronal nAChRs is presently limited. In this study, we determined structures of the transmembrane (TM) domains of the 伪4 and 尾2 subunits in lauryldimethylamine-oxide (LDAO) micelles using solution NMR spectroscopy. NMR experiments and size exclusion chromatography-multi-angle light scattering (SEC-MALS) analysis demonstrated that the TM domains of 伪4 and 尾2 interacted with each other and spontaneously formed pentameric assemblies in the LDAO micelles. The Na⁺ flux assay revealed that 伪4尾2 formed Na⁺ permeable channels in lipid vesicles. Efflux of Na⁺ through the 伪4尾2 channels reduced intra-vesicle Sodium Green鈩?fluorescence in a time-dependent manner that was not observed in vesicles without incorporating 伪4尾2. The study provides structural insight into the TM domains of the 伪4尾2 nAChR. It offers a valuable structural framework for rationalizing extensive biochemical data collected previously on the 伪4尾2 nAChR and for designing new therapeutic modulators.