At resting membrane potential, the NMDA receptor ion channel is blocked by extracellular Mg2+ ions and is unable to mediate ion permeation upon binding of ligands (glutamate, glycine, D-serine, NMDA). The voltage block is removed upon depolarization of the post-synaptic cell membrane and Mg2+ is expelled from the NMDA receptor pore (channel), resulting in activated ligand-bound NMDA receptors. The depolarization of the membrane may happen in response to activation of Ca2+ impermeable AMPA receptors, which facilitates Na+ influx, contributing to the unblocking of NMDA receptors. For review, please refer to Traynelis et al. 2010, Paoletti et al. 2013, and Iacobucci and Popescu 2017.