NMR structures of the transmembrane domains of the alpha4beta2 nAChR.
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Bondarenko V, Mowrey D, Tillman T, Cui T, Liu LT, Xu Y, Tang P
NMR structures of the transmembrane domains of the alpha4beta2 nAChR.
Biochim Biophys Acta. 2012 May;1818(5):1261-8. doi: 10.1016/j.bbamem.2012.02.008. Epub 2012 Feb 14.
- PubMed ID
- 22361591 [ View in PubMed]
- Abstract
The alpha4beta2 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 alpha4beta2 and other neuronal nAChRs is presently limited. In this study, we determined structures of the transmembrane (TM) domains of the alpha4 and beta2 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 alpha4 and beta2 interacted with each other and spontaneously formed pentameric assemblies in the LDAO micelles. The Na(+) flux assay revealed that alpha4beta2 formed Na(+) permeable channels in lipid vesicles. Efflux of Na(+) through the alpha4beta2 channels reduced intra-vesicle Sodium Green fluorescence in a time-dependent manner that was not observed in vesicles without incorporating alpha4beta2. The study provides structural insight into the TM domains of the alpha4beta2 nAChR. It offers a valuable structural framework for rationalizing extensive biochemical data collected previously on the alpha4beta2 nAChR and for designing new therapeutic modulators.