Amino terminal domain regulation of NMDA receptor function

N-Methyl-D-aspartate (NMDA) receptor function is modulated by a wide variety of compounds, several of which appear to bind to globular extracellular amino terminal subunit domains (ATDs). This review focuses on modulators with putative binding sites in ATDs of NMDA receptor subunits, and potential mechanisms by which these compounds exert their effects on receptor function. With an overview that stresses several themes, we explore evidence that the ATDs of NR2 subunits appear to bind modulatory compounds in the cleft of a clamshell-like structure that is analogous to the ligand-binding domain. This modulation influences NMDA receptor function only partially, is dependent on extracellular pH, and affects receptor desensitization. Modulation of the NMDA receptor by the ATD is considered within a framework of functional modularity of multisubunit ion channels. We also consider the potential importance of the ATD in assembly of the receptor.