State-specific inhibition of NMDA receptors by memantine provides insight into NMDAR channel blocker tolerability.

N-methyl-d-aspartate (NMDA) receptors (NMDARs) are key mediators of calcium ion (Ca2+) influx required for proper neuronal function. Excessive NMDAR-mediated Ca2+ influx is neurotoxic and associated with neurological disease. Memantine and ketamine, two NMDAR antagonists with overlapping binding sites in the NMDAR channel, are of high clinical interest. Whereas memantine is a well-tolerated Alzheimer's disease medication, ketamine is a fast-acting antidepressant with abuse potential and psychotomimetic effects. The mechanisms underlying the disparate tolerability of memantine and ketamine remain elusive. We show here that inhibition of recombinant and native NMDARs by memantine, but not ketamine, increases with increasing intracellular Ca2+ concentration ([Ca2+]i). [Ca2+]i-dependent inhibition results from stabilization of a desensitized receptor state and depends on NMDAR subtype. Neuroprotection assays and postsynaptic current recordings show that memantine, but not ketamine, preferentially inhibits NMDARs under neurotoxic conditions. Our results reveal a form of state-specific antagonism that allows for the selective targeting of NMDAR subpopulations involved in disease.