NMDA Receptors

Abstract

N‐methyl‐D‐aspartate (NMDA) receptors are one type of glutamate receptor. They play key roles in synaptic transmission and plasticity in the central nervous system. They are uniquely activated by simultaneous binding of the amino acids glycine and l ‐glutamate. These receptors are proteins that form an ion channel across the cell membrane, commonly formed by assembly of two glutamate‐binding GluN2 subunits and two glycine‐binding GluN1 subunits. The ion channel opens following receptor activation, allowing Na + and Ca 2+ ions to cross the cell membrane, thus translating the transient chemical signal provided by release of glutamate from a presynaptic neuron, into postsynaptic electrical and biochemical Ca 2+ signals. Crucially, the characteristics of NMDA receptor signalling depend on the receptor subunit composition, particularly the nature of the GluN2 subunits which can be of four different types, creating unique and important variations in properties that provide a rich diversity of NMDA receptor signalling in the brain. Key Concepts NMDA receptor functional diversity is determined by the receptor subunit composition. Key functional attributes of NMDA receptors are the Ca 2+ permeability and Mg 2+ block of the transmembrane ion channel and the slow kinetics of receptor activation which can last for hundreds of milliseconds. The receptor subunits are somewhat modular in nature with key functional attributes depending on particular domains of the subunit protein. Domain interactions are an emerging concept in understanding NMDA receptor structure–function relationships. Allosteric modulators of NMDA receptors can both enhance or inhibit receptor function and provide the future possibility of novel therapeutic approaches to diseases of the nervous system associated with altered NMDA receptor function.