Abstract
Several ion channels are thought to be directly modulated by nitric oxide (NO), but the molecular basis of this regulation is unclear. Here we show that the NMDA receptor (NMDAR)-associated ion channel was modulated not only by exogenous NO but also by endogenous NO. Site-directed mutagenesis identified a critical cysteine residue (Cys 399) on the NR2A subunit whose S-nitrosylation (NO+ transfer) under physiological conditions underlies this modulation. In cell systems expressing NMDARs with mutant NR2A subunits in which this single cysteine was replaced by an alanine, the effect of endogenous NO was lost. Thus endogenous S-nitrosylation can regulate ion channel activity.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Line
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Chromatography, High Pressure Liquid
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Cysteine / analogs & derivatives
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Cysteine / metabolism
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Cysteine / pharmacology
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Dose-Response Relationship, Drug
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Ethyl Methanesulfonate / analogs & derivatives
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Ethyl Methanesulfonate / pharmacology
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Humans
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Indicators and Reagents / pharmacology
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Ion Transport / drug effects
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Ion Transport / physiology*
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Mesylates / pharmacology
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Mutagenesis, Site-Directed
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N-Methylaspartate / antagonists & inhibitors
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N-Methylaspartate / pharmacology
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Nitric Oxide / metabolism*
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Nitric Oxide / pharmacology
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Nitroso Compounds / pharmacology
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Oocytes / cytology
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Patch-Clamp Techniques
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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S-Nitrosothiols*
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Transfection
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Xenopus laevis
Substances
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Indicators and Reagents
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Mesylates
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NMDA receptor A1
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NR2A NMDA receptor
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Nitroso Compounds
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Peptide Fragments
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Receptors, N-Methyl-D-Aspartate
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S-Nitrosothiols
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methanethiosulfonate ethylammonium
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(2-(trimethylammonium)ethyl)methanethiosulfonate
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Nitric Oxide
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N-Methylaspartate
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S-nitrosocysteine
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Ethyl Methanesulfonate
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Cysteine