Molecular basis of reactive oxygen species-induced inactivation of α4β2 nicotinic acetylcholine receptors

作者：Zhao, Junjun; Zheng, Yan; Xue, Fenqin; Chang, Yongchang; Yang, Hui^*; Zhang, Jianliang^*

来源：Free Radical Biology and Medicine, 2016, 97: 520-530.

DOI：10.1016/j.freeradbiomed.2016.07.012

• Neuronal nicotinic acetylcholine receptors
• Reactive oxygen species
• Parkinson's disease

The alpha 4 beta 2 neuronal nicotinic acetylcholine receptors (nAChRs) are the most widespread heteromeric nAChR subtype in the brain, mediating fast synaptic transmission. Previous studies showed that alpha 4 beta 2 nAChRs could be inactivated by reactive oxygen species (ROS), but the underlying mechanism is still obscure. We found that H2O2 induced the rundown of ACh-evoked currents in human alpha 4 beta 2 nAChRs and the replacement of the conserved cysteine in the M1-M2 linker of either alpha 4 Cys245 or beta 2 Cys237 with an alanine residue could prevent the current rundown. Structurally, alpha 4 Cys245 and beta 2 Cys237 are hypothesized to be in close proximity when the receptor is activated. Western blotting results showed that alpha 4 and beta 2 subunits were cross-linked when the agonist-bound receptor encountered H2O2, which could be prevented by the substitution of the conserved cysteine in the M1-M2 linker to an alanine. Thus, when agonist bound to the receptor, alpha 4 Cys245 and beta 2 Cys237 came close to each other and ROS oxidized these conserved cysteines, leading subunits to be cross-linked and trapping alpha 4 beta 2 nAChRs into the inactivation state. In addition, we mimicked an experimental Parkinson's disease (PD) model in PC12 cells and found that ROS, generated by 6-hydroxydopamine (6-OHDA), could cause the current rundown in alpha 4 beta 2 nAChRs, which may play a role in PD.

• 出版日期2016-8
• 单位首都医科大学