Molecular mechanism of calcium permeability and magnesium block in NMDA receptors

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.