Modulating synaptic NMDA receptors

Recent structural information on ligand-gated glutamate receptors and newly-discovered clinical uses for NMDA receptor antagonists has renewed interest in understanding the mechanisms of drug action at these receptors. Although the voltage-dependence and calcium permeability of NMDA receptors are well-studied, the mechanisms affecting the time course of synaptic NMDA receptor activation may be of more therapeutic value by serving as a rheostat for the total synaptic response. The NMDA receptor-mediated EPSC time course has been thought of as a fixed parameter based simply on receptor subunit composition as variably constrained by anatomical and developmental expression patterns, albeit subject to modification by kinetic behaviors such as modal gating. However, the EPSC time course also can be manipulated by endogenous and exogenous ligands. In this commentary we discuss insights into the in situ composition and kinetic behavior of synaptic NMDA receptors and propose new opportunities to target modulatory sites on NMDA receptors and to develop useful therapeutics. The emerging data on the atomic structure of NMDA receptors and knowledge of the kinetics of native receptors in neurons provide a roadmap in this regard. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’.