NMDA receptors: linking physiological output to biophysical operation

Key Points NMDA receptor isoforms respond to glutamate with distinct kinetics and have dynamic, complex and incompletely delineated expression profiles; precise mechanistic information for specific receptor isoforms is derived from recombinant preparations. Functional attributes of recombinant receptor current match well to those of the NMDA receptor-mediated response recorded from synaptic and non-synaptic native receptors. Kinetic models derived from one-channel recordings reproduce all known features of the macroscopic response and reveal novel biophysical properties that underlie physiologically salient features of the synaptic current. The NMDA receptor response amplitude and ionic charge transfer, which initiate synaptic plasticity, depend on stimulation frequency as predicted by the kinetic model. The biphasic decay time of the NMDA receptor synaptic response, which sets the window for coincident depolarization, reflects the proportion of receptors gating in distinct kinetic modes. This insight was afforded by statistical evaluation of single-channel behaviour. Assigning molecular structures to the kinetic states postulated by statistically derived models of NMDA receptor activation is an active area of research. Kinetic models of NMDA receptor activation derived from single-molecule observations explain the biologically salient features of the excitatory current as a dynamic sequence of quasi-stable receptor states. In this Review, Iacobucci and Popescu discuss how these models will help to match emerging atomic structures with biologically important functional states. NMDA receptors are preeminent neurotransmitter-gated channels in the CNS, which respond to glutamate in a manner that integrates multiple external and internal cues. They belong to the ionotropic glutamate receptor family and fulfil unique and crucial roles in neuronal development and function. These roles depend on characteristic response kinetics, which reflect the operation of the receptors. Here, we review biologically salient features of the NMDA receptor signal and its mechanistic origins. Knowledge of distinctive NMDA receptor biophysical properties, their structural determinants and physiological roles is necessary to understand the physiological and neurotoxic actions of glutamate and to design effective therapeutics.