The NMDA receptor complex

The NMDA receptor complex 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Fundamental & Clinical Pharmacology Wiley

The NMDA receptor complex

Fundamental & Clinical Pharmacology, Volume 7 (8) – Nov 1, 1993

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Publisher
Wiley
Copyright
1993 Société Française de Pharmacologie et de Thérapeutique
ISSN
0767-3981
eISSN
1472-8206
D.O.I.
10.1111/j.1472-8206.1993.tb01036.x
Publisher site
See Article on Publisher Site

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.

Journal

Fundamental & Clinical PharmacologyWiley

Published: Nov 1, 1993

References

  • Nitric oxide, a novel neuronal messenger
    Bredt, Bredt; Snyder, Snyder
  • Glutamate: a neurotransmitter in mammalian brain
    Fonnum, Fonnum
  • N‐methyl‐D‐aspartate recognition site ligands modulate activity at the coupled glycine recognition site
    Hood, Hood; Compton, Compton; Monahan, Monahan
  • A physiologist's view of the N‐methyl‐D‐aspartate receptor: an allosteric ion channel with multiple regulatory sites
    Mayer, Mayer; Viklicky, Viklicky; Sernegor, Sernegor
  • The excitatory amino acid receptors: their classes, pharmacology and distinct properties in the function of the central nervous system
    Monaghan, Monaghan; Bridges, Bridges; Cotman, Cotman
  • Cooperative modulation of 3 H‐MK‐801 binding to the N‐methyl‐D‐aspartate receptor‐ion channel complex by L‐glutamate, glycine and polyamines
    Ransom, Ransom; Stec, Stec
  • Polyamines regulate glycine interaction with the N‐methyl‐D‐aspartate receptor
    Ransom, Ransom; Deschenes, Deschenes
  • Reduction of NMDA receptors with dithiothreitol increases 3 H‐MK‐801 binding and NMDA‐induced Ca 2+ fluxes
    Reynolds, Reynolds; Rush, Rush; Aizenman, Aizenman
  • Release of neurotransmitter amino acids from synaptosomes: enhancement of calcium‐independent efflux by oleic and arachidonic acids
    Rhoads, Rhoads; Osburn, Osburn; Peterson, Peterson; Raghupathy, Raghupathy
  • Glutamate and the pathophysiology of hypoxic‐ischemic brain damage
    Rothman, Rothman; Olney, Olney

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