On the mechanism of calcium permeability and magnesium block in NMDA receptors - a central molecular paradigm in neuroplasticity

Neuroplasticity is a fundamental cellular mechanism underlying learning and memory formation and is primed by the coincidental detection of neurotransmitter release from the presynapse and the subsequent calcium influx upon voltage change in the postsynaptic membrane (Bliss and Collingridge, 1993). Molecular assemblies that achieve these events are N-methyl-D-aspartate receptors (NMDARs), which bind the neurotransmitter glutamate and a co-agonist, either glycine or D-serine, and allow Ca ²⁺ influx upon relief of the Mg ²⁺ channel blockade by membrane depolarization. However, the molecular basis governing Ca ²⁺ permeability and Mg ²⁺ blockade in NMDAR remains limited. Here, we demonstrate that Ca²⁺ permeation through the narrow constriction of the cation selectivity filter involves partial dehydration, as evidenced by multiple Ca²⁺ binding sites captured using single-particle cryo-electron microscopy (cryo-EM). In contrast, Mg ²⁺ binds outside of the selectivity filter through the water network by remaining hydrated, thereby serving as a channel blocker. Furthermore, we show that the lipid network around the selectivity filter influences the stability of Mg ²⁺ binding. Our study details the critical transmembrane chemistry of NMDAR for initiating neuroplasticity.