Extrasynaptic NMDA receptor

Extrasynaptic NMDA receptors are glutamate-gated neurotransmitter receptors that are localized to non-synaptic sites on the neuronal cell surface.^[1][2] In contrast to synaptic NMDA receptors that promote acquired neuroprotection and synaptic plasticity, extrasynaptic NMDA receptors are coupled to activation of death-signaling pathways.^[3] Extrasynaptic NMDA receptors are responsible for initiating excitotoxicity and have been implicated in the etiology of neurodegenerative diseases, including stroke, Huntington’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).^{[4][5][6][7][8]}

Extrasynaptic NMDA receptors form a death signaling complex with the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 complex is considered central to glutamate excitotoxicity.^[9] NMDAR/TRPM4 interaction interface inhibitors (also known as 'interface inhibitors') disrupt the NMDAR/TRPM4 complex thereby detoxifying extrasynaptic NMDA receptors. In mouse disease models, interface inhibitors protect against stroke induced brain damage and retinal ganglion cell degeneration.^[10][11]