Targeting the N-Methyl-d-Aspartate Receptor for Chronic Pain Management  Kim Fisher, PhD, Terence J Coderre, PhD, Neil A Hagen, MD, FRCPC  Journal of Pain and Symptom Management  Volume 20, Issue 5, Pages 358-373 (November 2000) DOI: 10.1016/S0885-3924(00)00213-X

Fig. 1 Schematic diagram representing the NMDA receptor complex. The NMDA receptor is most likely based on the assembly of NMDA Receptor 1 subunits, which contain binding sites for various transmitters and ions that influence its function, and NMDA Receptor 2 subunits, which influence the sensitivity of these binding sites. Cloned NMDA receptors have an extracellular N terminus, an intracellular C terminus, and four transmembrane domains. The second transmembrane domain has been described as taking a hairpin turn and is thought to line the pore of the receptor-linked ion channel, which is permeable to calcium (Ca2+), sodium (Na+), and potassium (K+). An asparagine residue in the second transmembrane domain has been proposed to regulate Ca2+ permeability and magnesium (Mg2+) binding. Mg2+ produces a voltage-dependent block of the NMDA receptor channel that is present at resting membrane potentials. A binding site for phencyclidine-like drugs (PCP) is present within the lumen of the channel, and these agents act as open channel blockers. Glycine acts as a co-agonist at a binding site that is allosterically coupled to the NMDA binding site, which is formed between the two extracellular segments. There may be as many as three extracellular binding sites for polyamines which enhance currents through the NMDA channel and a distinct site for zinc (Zn2+), which inhibits responses to NMDA. There is also a redox site (most likely extracellular), which regulates the NMDA channel with reducing agents producing an increase of NMDA currents and oxidizing agents producing a decrease of NMDA currents. Finally, there are four or five residues on the intracellular C terminal domain that can be phosphorylated by protein kinase C (PKC), which leads to enhanced NMDA currents Journal of Pain and Symptom Management 2000 20, 358-373DOI: (10.1016/S0885-3924(00)00213-X)