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      Mitochondrial Reactive Oxygen Species Inactivate Neuronal Nicotinic Acetylcholine Receptors and Induce Long-Term Depression of Fast Nicotinic Synaptic Transmission

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          Abstract

          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.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneuro
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          13 February 2008
          : 28
          : 7
          : 1733-1744
          Affiliations
          [1]Department of Physiology, McGill University, Montreal, Quebec, Canada H3G 1Y6
          Author notes
          Correspondence should be addressed to Prof. Ellis Cooper, Department of Physiology, McGill University, McIntyre Medical Science Building, 3655 Promenade Sir William Osler, Montreal, Quebec, Canada H3G 1Y6. ellis.cooper@ 123456mcgill.ca
          Article
          PMC6671543 PMC6671543 6671543 3315100
          10.1523/JNEUROSCI.5130-07.2008
          6671543
          18272694
          356fb6ce-8565-43d9-a767-0930bd9dd400
          Copyright © 2008 Society for Neuroscience 0270-6474/08/281733-12$15.00/0
          History
          : 14 June 2007
          : 21 December 2007
          : 21 December 2007
          Categories
          Articles
          Cellular/Molecular

          nerve growth factor,desensitization,autonomic nervous system,oxidative stress,sympathetic neurons,mitochondrial ROS,Fenton reaction,antimycin-A

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