Abstract
Many N-methyl-D-aspartate receptor (NMDAR) channel blockers that have therapeutic potential can be trapped in the closed state. Using a combination of the substituted cysteine accessibility method and open channel blockers, we found that the M3 segment forms the core of the extracellular vestibule, including a deep site for trapping blockers. The M3 segment, as well as more superficial parts of the extracellular vestibule, undergo extensive remodeling during channel closure, but do not define the activation gate, which is located deeper in the pore. Rather, the pore walls lining the extracellular vestibule constrict during channel closure. This movement is essential for coupling ligand binding to activation gate opening and accounts for the different mechanisms of open channel block, including trapping.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Aminacrine / pharmacology
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Animals
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Cell Membrane / drug effects
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Cell Membrane / metabolism
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Central Nervous System / drug effects
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Central Nervous System / metabolism*
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Cysteine / chemistry
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Cysteine / drug effects
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Cysteine / genetics
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Drug Interactions / physiology
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Excitatory Amino Acid Antagonists / pharmacology*
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Extracellular Space / chemistry*
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Extracellular Space / drug effects
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Female
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Glutamic Acid / metabolism
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Glutamic Acid / pharmacology
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Ion Channel Gating / drug effects
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Ion Channel Gating / physiology*
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Membrane Potentials / drug effects
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Membrane Potentials / physiology
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Mutagens / pharmacology
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Mutation / drug effects
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Mutation / physiology
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Oocytes
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Protein Structure, Tertiary / drug effects
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Protein Structure, Tertiary / physiology
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Receptors, N-Methyl-D-Aspartate / chemistry*
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Receptors, N-Methyl-D-Aspartate / drug effects*
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Receptors, N-Methyl-D-Aspartate / genetics
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Synaptic Transmission / drug effects
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Synaptic Transmission / physiology*
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Xenopus laevis
Substances
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Excitatory Amino Acid Antagonists
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Mutagens
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Receptors, N-Methyl-D-Aspartate
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Glutamic Acid
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Aminacrine
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Cysteine