Steigerwald, Ruben, Epstein, Max, Chou, Tsung-Han, Simorowski, Noriko, Furukawa, Hiro (May 2026) Molecular mechanism of calcium permeability and magnesium block in NMDA receptors. Nature Neuroscience. ISSN 1097-6256 (Public Dataset)
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Abstract
Hebbian neuroplasticity, which is thought to be a cellular substrate of learning and memory, can occur by means of coincidental detection of presynaptic neurotransmitter release and Ca2+ influx upon postsynaptic depolarization. This is mediated at a molecular level by N-methyl-D-aspartate-type glutamate receptors, which bind glutamate and glycine and facilitate Ca2+ influx upon relief of Mg2+ channel block during membrane depolarization. However, the structural mechanism underlying Ca2+ permeability and Mg2+ blockade in N-methyl-D-aspartate-type glutamate receptors has yet to be fully elucidated. Here we demonstrate using single-particle cryo-electron microscopy that Ca2+ permeation through the narrow constriction of the cation selectivity filter involves partial dehydration, as evidenced by several Ca2+ binding sites. In contrast, Mg2+ binds outside of the selectivity filter through a water network and remains hydrated, thereby acting as a channel blocker. Furthermore, the lipid network around the selectivity filter influences the stability of Mg2+ binding in a voltage-dependent manner. Our study details the transmembrane chemistry essential for initiating neuroplasticity.
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