Subunit- and site-specific pharmacology of the NMDA receptor channel

N-Methyl-D-aspartate (NMDA) receptor channels play important roles in vario us physiological functions such as synaptic plasticity and synapse formatio n underlying memory, learning and formation of neural networks during devel opment. They are also important for a variety of pathological states includ ing acute and chronic neurological disorders, psychiatric disorders, and ne uropathic pain syndromes. cDNA cloning has revealed the molecular diversity of NMDA receptor channels . The identification of multiple subunits with distinct distributions, prop erties and regulation, implies that NMDA receptor channels are heterogeneou s in their pharmacological properties, depending on the brain region and th e developmental stage. Furthermore, mutation studies have revealed a critic al role for specific amino acid residues in certain subunits in determining the pharmacological properties of NMDA receptor channels. The molecular he terogeneity of NMDA receptor channels as well as their dual role in physiol ogical and pathological functions makes it necessary to develop subunit- an d site-specific drugs for precise and selective therapeutic intervention. This review summarizes from a molecular perspective the recent advances in our understanding of the pharmacological properties of NMDA receptor channe ls with specific references to agonists binding sites, channel pore regions , allosteric modulation sites for protons, polyamines, redox agents, Zn2+ a nd protein kinases/phosphatases. (C) 1999 Elsevier Science Ltd. All rights reserved.