Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants

Interface targeting skirts excitotoxicity Nearly all attempts to use traditional N -methyl- d -aspartate receptor (NMDAR) antagonists to treat neurodegenerative diseases have failed. This is because NMDARs are not only promoters of neuronal death but also have essential physiological roles in synaptic plasticity and cognitive functions such as learning and memory. Yan et al. explored the structural basis of NMDAR coupling to neuronal cell death (see the Perspective by Jones). The death-promoting activity, but not the essential physiological function, was mediated by the physical interaction of NMDARs with TRPM4, a calcium-impermeable ion channel activated by intracellular calcium, depolarization, and temperature. A subsequent structure-based computational drug screen led to the discovery of neuroprotective small molecules that block the NMDAR-TRPM4 interaction interface but spare the critical healthy NMDAR function. Science , this issue p. eaay3302 ; see also p. 168