The NMDA receptor complex

Abstract

Summary— The synaptic responses elicited by glutamate and aspartate in the CNS are mediated by distinct groups of receptors which include the ionotropic NMDA receptor. The NMDA receptor is activated by high-strength synaptic input and produces relatively sustained depolarization which can lead to repetitive burst firing. These characteristics allow it to be involved in the maintainance of rhythmic neuronal activity and in the modulation of synaptic efficacy and plasticity. Overstimulation of the NMDA receptor appears to play a pivotal role in the physiopathology of ischemic brain injury. The NMDA receptor contains an integral cationic channel which is highly permeable to Ca²⁺ as well as to Na+ and K+. This receptor has several domains in addition to the NMDA recognition site: i) a divalent cation binding site within the channel pore, at which Mg²⁺ ions bind, ii) a binding site recognized by dissociative anesthetics and MK-801 within the channel; and iii) modulatory sites sensitive to glycine, Zn²⁺ and polyamines. The NMDA receptor is strictly controlled by Mg²⁺ ions in a voltage-dependent manner. Moreover, it is modulated by protons, by changes in the redox state and by endogenous physiological substances, eg NO and arachidonic acid. Selective antagonists now exist for the NMDA recognition site and glycine and polyamine modulatory sites. Molecular cloning of the NMDA receptor has identified a subunit termed NMDA-R1 and four additional subunits (NMDA-R2A through NMDA-R2D). Functionally distinct NMDA receptor subtypes are formed by heteromeric assembly of NMDA-R1 with NMDA-R2 subunits. NMDA receptor subunits contain consensus phosphorylation sites for protein kinases at the cytoplasmic domain. The high Ca²⁺ permeability and sensitivity to channel block by Mg²⁺ are imparted by asparagine residues in a putative channel-forming segment of the protein transmembrane 2. The knowledge of the molecular structure of the NMDA receptor will help to understand the molecular mechanisms responsible for its regulatory features and the molecular bases of neurotoxicity.