Abstact

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.