Science, Medicine, and the Anesthesiologist

Glutamate-induced excitatory synaptic transmission, vital for brain function, is partly mediated by N-methyl-d-aspartate receptors (NMDARs), which are critical in synaptic plasticity and learning and memory. NMDARs are ligand-gated ion channels composed of GluN1 and GluN2 (2A-2D) subunits. Their dysfunction is linked to diseases like dementia, stroke, and chronic pain. GluN2B is upregulated in chronic pain and contributes to its pathology. Unlike other glutamate receptors, NMDARs require both ligand binding and membrane depolarization to remove the Mg²⁺ block and open the channel. The authors used electron cryomicroscopy to reveal the structure of the GluN1-GluN2B NMDAR in its open state, bound to a positive allosteric modulator. This interaction alters the symmetry of the transmembrane domain. Interestingly, binding glycine or glutamate alone induces distinct GluN1-GluN2B dimer arrangements but does not trigger channel opening. The research also sheds light on the unique dual-agonist requirement of NMDAR, explaining why glycine or d-serine is necessary to prime the receptor as positive allosteric modulator for glutamate-induced activation. This mechanism distinguishes NMDAR from other ionotropic glutamate receptors. The study also explains how ketamine binds to NMDAR.

Take home message: The study uncovers a key mechanism in NMDAR gating, offering insights for developing pharmacological strategies to manage chronic pain.