The structure of NMDA receptors at atomic resolution is not known. However, it is widely accepted that NMDA receptors assemble as hetero-tetramers of two obligatory NR1 subunits and two regionally localised NR2 subunits. A related gene family of NR3 A-C subunits can substitute for NR2 subunits in specific brain regions and has an inhibitory effect on receptor activity. Multiple receptor isoforms with disinct brain distributions and functional properties arise by selective splicing of the NR1 transcripts and differential expression of the NR2 subunits. Each receptor subunit has modular design and each structural module also represents a functional unit.
The extracellular domain contains two globular structures: a modulatory domain and a ligand-binding domain. NR1 subunits bind the co-agonist glycine and NR2 subunits bind the neurotransmitter glutamate. The agonist-binding module links to a membrane domain which consists of three transmembrane segments and a re-entrant loop. The membrane domain contributes residues to the channel pore and is responsible for the receptor's high unitary conductance, high calcium permeability, and voltage-dependent magnesium block. Each subunit has an extensive cytoplasmic domain which contains residues that can be directly modified by a series of protein kinases and protein phosphatases, as well as residues which interact with a large number of structural, adaptor and scaffolding proteins.
The NMDA receptor requires both glutamate and the co-agonist glycine for the efficient opening of the ion channel. A third requirement is membrane depolarisation. A change in electrical potential towards equilibrium between the two sides of the membrane in which the receptor sits makes it more likely that the ion channel in the NMDA receptor will open by expelling the Mg2+ ion that blocks the channel from the outside.
Synthetic antagonists include:
AP5 (2-amino-5-phosphonopentanoate), a competitive glutamate antagonist selective for the NMDA receptor
Phencyclidine, all of which are non-competitive channel blockers
Dextromethorphan, a synthetic analogue of codeine, the d-isomer of 3-methoxy-N-methylmorphine
Memantine is an NMDA receptor antagonist used in the treatment of Alzheimer's disease.
The NMDA receptor is modulated by a number of endogenous and exogenous compounds. Mg2+ not only blocks the NMDA channel in a voltage-dependent manner but also potentiates NMDA-induced responses at positive membrane potentials.
Na+, K+ and Ca2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. Zn2+ blocks the NMDA current in a non-competitive and voltage-independent manner. The activity of NMDA receptors is also sensitive to the changes in H+ concentration, and is partially inhibited by the ambient concentration of H+ under physiological conditions.
Role of the NMDA receptor
NMDA receptor activation triggers a cascade of events leading to sensitisation of dorsal horn wide dynamic range neurones. There is a significant increase in intracellular calcium and activation of protein kinases and phosphorylating enzymes. NMDA receptor stimulation will also increase the production of spinal phospholipase and induce the production of nitric oxide synthetase. The prostaglandins and nitric oxide which are subsequently produced and released into the extracellular milieu can facilitate further release of excitatory amino acids and neuropeptides from primary afferent pain fibres. The NMDA receptor antagonists ketamine and dextromethorphan can block this cascade of events which contribute to sensitisation.