Voltage‐dependent gating of NR1/2B NMDA receptors

Ligand‐gated ion channels are activated by agonist binding, but may also be modulated by membrane voltage. N ‐Methyl‐ d ‐aspartate receptors (NMDARs) exhibit especially strong voltage dependence due to channel block by external Mg 2+ (Mg o 2+ ) . Here we demonstrate that activity of NMDARs composed of NR1 and NR2B subunits (NR1/2B receptors) is enhanced by depolarization even in 0 Mg o 2+ , causing slow current relaxations in response to rapid voltage changes. We present a kinetic model of receptor activation that incorporates voltage‐dependent gating‐associated NR2B subunit conformational changes. The model accurately reproduces current relaxations during depolarizations and subsequent repolarizations in 0 Mg o 2+ . Model simulations in physiological Mg o 2+ concentrations show that voltage‐dependent receptor gating also underlies the slow component of Mg o 2+ unblock, a phenomenon that previously was shown to influence Mg o 2+ unblock kinetics during dendritic spikes. We propose that voltage‐dependent gating of NR1/2B receptors confers enhanced voltage and time dependence on NMDAR‐mediated signalling.