Site of ketamine action on the NMDA receptor

Ketamine, an antagonist of N-methyl-d-aspartate receptors (NMDARs), produces rapid and sustained reduction of symptoms in patients with treatment-resistant depression. NMDARs are critical for neural network formation, neuronal plasticity, higher brain functions, and pathophysiology of neurodegenerative and psychiatric disorders. Recent studies have identified functional domains of diverse NMDAR subunits, as well as the site of ketamine action on NMDARs. The site of ketamine action overlaps with the site of physiological voltage-dependent Mg²⁺ block. Furthermore, different NMDAR GluN2 subunits contribute differentially to the sensitivity of ketamine. High-resolution analyses of the structure of the action site of ketamine on NMDARs and the mechanisms of ketamine action in vivo will contribute to the development of novel and effective antidepressant drugs.