Mitochondrial reactive oxygen species inactivate neuronal nicotinic acetylcholine receptors and induce long-term depression of fast nicotinic synaptic transmission.
Neuronal nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels implicated in a variety of cognitive, motor, and sensory behaviours, are targeted to compartments rich in mitochondria, particularly postsynaptic domains and presynaptic terminals, exposing these receptors to reactive oxygen species (ROS) generated by oxidative phosphorylation. In addition, these receptors can become exposed to ROS during the progression of certain neurodegenerative diseases. Because ROS are known to modify several membrane proteins, including some types of ion channels, it raises the question of whether elevations in cytosolic ROS alter the function of nAChRs. To address this, we elevated ROS in cultured sympathetic neurons, directly by perfusing neurons intracellularly with ROS, indirectly by blocking the mitochondrial electron transport chain, or noninvasively by transient NGF removal; we then simultaneously measured changes in cytosolic ROS levels and whole-cell ACh-evoked currents. In addition, we elevated cytosolic ROS in postganglionic neurons in intact ganglia and measured changes in nerve-evoked EPSPs. Our experiments indicate that mild elevations in cytosolic ROS, including that produced by transient interruption of NGF signaling, induce a use-dependent, long-lasting rundown of ACh-evoked currents on cultured sympathetic neurons and a long-lasting depression of fast nerve-evoked EPSPs. We show that these effects of cytosolic ROS are specific to nAChRs on neurons and do not cause rundown of ACh-evoked currents on muscle. Our results demonstrate that elevations in cytosolic ROS inactivate neuronal nAChRs in a use-dependent manner and suggest that mild oxidative stress impairs mechanisms mediated by cholinergic nicotinic signaling at neuronal-neuronal synapses.
Campanucci
Verónica A
VA
Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6.
Krishnaswamy
Arjun
A
Cooper
Ellis
E
D000818:Animals; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D005071:Evoked Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*
D017382:Reactive Oxygen Species; D011978:Receptors, Nicotinic