Molecular Basis Of Reactive Oxygen Species-Induced Inactivation Of Î±4Î²2 Nicotinic Acetylcholine Receptors
The Î±4Î²2 neuronal nicotinic acetylcholine receptors (nAChRs) are the most widespread heteromeric nAChR subtype in the brain, mediating fast synaptic transmission. Previous studies showed that Î±4Î²2 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 Î±4Î²2 nAChRs and the replacement of the conserved cysteine in the M1â€“M2 linker of either Î±4 Cys245 or Î²2 Cys237 with an alanine residue could prevent the current rundown. Structurally, Î±4 Cys245 and Î²2 Cys237 are hypothesized to be in close proximity when the receptor is activated. Western blotting results showed that Î±4 and Î²2 subunits were cross-linked when the agonist-bound receptor encountered H2O2, which could be prevented by the substitution of the conserved cysteine in the M1â€“M2 linker to an alanine. Thus, when agonist bound to the receptor, Î±4 Cys245 and Î²2 Cys237 came close to each other and ROS oxidized these conserved cysteines, leading subunits to be cross-linked and trapping Î±4Î²2 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 Î±4Î²2 nAChRs, which may play a role in PD.
Free Radical Biology and Medicine
Digital Object Identifier (DOI)
Zhao, Junjun; Zheng, Yan; Xue, Fenqin; Chang, Yongchang; Yang, Hui; and Zhang, Jianliang, "Molecular Basis Of Reactive Oxygen Species-Induced Inactivation Of Î±4Î²2 Nicotinic Acetylcholine Receptors" (2016). Neurobiology. 61.