title: Reactive oxygen species inactivate neuronal nicotinic acetylcholine receptors through a highly conserved cysteine near the intracellular mouth of the channel: implications for diseases that involve oxidative stress.
abstract: An intriguing feature of several nicotinic acetylcholine receptors (nAChRs) on neurons is that their subunits contain a highly conserved cysteine residue located near the intracellular mouth of the receptor pore. The work summarized in this review indicates that α3β4-containing and α4β2-containing neuronal nAChRs, and possibly other subtypes, are inactivated by elevations in intracellular reactive oxygen species (ROS). This review discusses a model for the molecular mechanisms that underlie this inactivation. In addition, we explore the implications of this mechanism in the context of complications that arise from diabetes. We review the evidence that diabetes elevates cytosolic ROS in sympathetic neurons and inactivates postsynaptic α3β4-containing nAChRs shortly after the onset of diabetes, leading to a depression of synaptic transmission in sympathetic ganglia, an impairment of sympathetic reflexes. These effects of ROS on nAChR function are due to the highly conserved Cys residues in the receptors: replacing the cysteine residues in α3 allow ganglionic transmission and sympathetic reflexes to function normally in diabetes. This example from diabetes suggests that other diseases involving oxidative stress, such as Parkinson's disease, could lead to the inactivation of nAChRs on neurons and disrupt cholinergic nicotinic signalling.
authors.affiliation: Department of Physiology, McGill University, Montreal, Qc, Canada.
authors.forename: Arjun
authors.initials: A
authors.lastname: Krishnaswamy
authors.forename: Ellis
authors.initials: E
authors.lastname: Cooper
mesh_terms: D003545:Cysteine / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism; D005728:Ganglia, Sympathetic / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic; D003545:Cysteine