NMDA receptors (N-methyl-D-aspartate receptors) are glutamate-gated ion channels critical for synaptic transmission, plasticity, and learning. [@geneprotein] These receptors are unique among ionotropic glutamate receptors in requiring both glutamate binding and membrane depolarization for activation, making them coincidence detectors for synaptic activity. [@auto_37988826] NMDA receptors are central to most forms of synaptic plasticity, including [long-term potentiation](/mechanisms/long-term-potentiation) (LTP) and long-term depression (LTD), processes fundamental to memory and cognition.
In neurodegenerative diseases, [NMDA receptor](/entities/nmda-receptor) dysfunction is a major contributor to excitotoxicity — the pathological overactivation of glutamate receptors leading to calcium overload and neuronal death. Both excessive activation and impaired function of NMDA receptors contribute to neurodegeneration in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), and [stroke](/diseases/stroke). [@auto_32640967] [@auto_38494274]
Structure
NMDA receptors are heterotetramers composed of: [@auto_38727900]
GluN1 subunit (encoded by [GRIN1](/genes/grin1)): Required for functional channels
GluN2A-D subunits (encoded by [GRIN2A](/genes/grin2a), [GRIN2B](/genes/grin2b), etc.): Modulate properties
GluN3A-B subunits: Modulatory subunits
Key structural features:
Agonist binding domains (S1-S2): Bind glutamate (on GluN2) and glycine/D-serine (on GluN1)
Transmembrane domains (M1-M4): Form the ion channel pore
C-terminal intracellular domains: Regulate trafficking, scaffolding, and signaling
Polyamine block: Magnesium block requires depolarization to relieve [@auto_32718032]
Normal Function in the Nervous System
Synaptic Transmission
NMDA receptors mediate:
Excitatory transmission: Major contributor to excitatory postsynaptic currents
Calcium influx: Highly permeable to Ca2+ (unlike AMPA receptors)
Voltage dependence: Magnesium block relieved by depolarization
Kinetic properties: Slow activation and deactivation kinetics
Synaptic Plasticity
NMDA receptors are required for:
[Long-term potentiation](/mechanisms/long-term-potentiation) (LTP): Activity-dependent strengthening of synapses