Atomic insights into the physiological and functional diversity of NMDA receptors

N-methyl-D-aspartate receptors (NMDARs) are essential for brain development, memory processes, and cognition. They primarily act as coincidence detectors at the synapse, integrating presynaptic glutamate release and postsynaptic membrane depolarization to open the channel gate. This allows the influx of cations (mainly calcium) into the postsynaptic neuron and triggers downstream signaling for synaptic plasticity. These receptors exhibit significant diversity in atomic structure, subunit composition, pharmacological properties, and biophysical characteristics. Advances in cryo-electron microscopy (cryo-EM) imaging have unlocked the structures of most recombinant NMDAR subtypes, providing a framework to understand their gating and pharmacological diversity. Furthermore, the ability to extract native NMDARs from rodent brain now positions the field to uncover their unique stoichiometry, assembly, and physiology in vivo. This review presents a synthesis of the emerging understanding of NMDAR physiological diversity and subtype-selective negative and positive allosteric modulation at atomic resolution, and it discusses potential directions for designing therapeutics based on these insights.