Allosteric inhibition of NMDA receptors by low dose ketamine.
Molecular psychiatry March 1, 2025 Jamie A Abbott, Han Wen, Beiying Liu et al. 14 citations
Ketamine produces rapid antidepressant effects at low doses, but the molecular targets responsible are debated. This study used electrophysiology, mutagenesis, and modeling to show that at nanomolar concentrations, ketamine binds to hydrophobic sites on NMDA receptors distinct from its known pore-blocking site. This binding stabilizes receptors in pre-open states, reducing gating in a voltage- and pH-dependent manner. Importantly, this allosteric inhibition spares brief synaptic activations but preferentially reduces currents from receptors activated tonically by ambient neurotransmitters. These hydrophobic sites may explain ketamine's unique clinical effects and offer targets for developing safer neuroactive drugs.