2003B15 Briefly describe the N-methyl d-aspartate (NMDA) receptor
and its physiological role in the central nervous system.

· General description

· Activation process

· Physiological role

Type	· Ligand-gated voltage-dependent glutamate receptor (i.e. both are required for its activation) · Others: AMPA, kainate)
Location	· Spinal cord: especially dorsal horn 2° nociceptive afferents · Brain: especially hippocampus
Structure	· Transmembrane, tetrameric (in vivo) · 2 x NR1 subunits (obligatory) – binds glycine · 2 x NR2 subunits (modulatory) – binds glutamate · Central ion channel pore with Mg²⁺ plug
Binding sites	· Glutamate site (agonist) · Glycine site (coagonist) · Phencyclidine site (within the pore): ketamine, PCP (non-competitive antagonists) · N₂O and Xe: site unknown (non-competitive antagonists)

1.Priming

· Activation of adjacent AMPA or NK-1 receptors

· Partial depolarisation -> removal of Mg²⁺ plug

2.Coactivation

· Binding of glycine

3.Activation

· Binding of glutamate

· Ion flux (Ca²⁺ influx > Na⁺ influx = K⁺ efflux)

· Cell-dependent downstream effects

Central sensitisation

· Gain of function of wide dynamic range 2° afferents at the dorsal horn

· Inflamed tissue, damaged nerve -> NMDA activation +++

· Short term: ↑receptor excitability = wind up

· Long term: ↑↓gene transcription -> synaptic reinforcement = potentiation

· Hence hyperalgaesia, allodynia, chronic pain

Neuroplasticity

· e.g. learning, memory

· Repetition -> high frequency NMDA activation

· Activity-dependent facilitation -> long-term potentiation

· Activity-dependent inhibition -> long-term depression

Excitotoxicity

· Ischaemia -> failure of ion homeostasis -> depolarisation -> release of glutamate

· NMDA activation+++ -> ↑ICF [Ca²⁺]

· ↑Activity of lytic enzymes, apoptosis

· Mitochondrial dysfunction, further ↓[ATP]