Ruben Steigerwald, Max Epstein, Tsung‐Han Chou, Noriko Simorowski, Hiro Furukawa
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 Ca 2+ 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 Ca 2+ influx upon relief of Mg 2+ channel block during membrane depolarization. However, the structural mechanism underlying Ca 2+ permeability and Mg 2+ 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 Ca 2+ permeation through the narrow constriction of the cation selectivity filter involves partial dehydration, as evidenced by several Ca 2+ binding sites. In contrast, Mg 2+ 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 Mg 2+ binding in a voltage-dependent manner. Our study details the transmembrane chemistry essential for initiating neuroplasticity.