Desensitization of NMDA Receptor Channels Is Modulated by Glutamate Agonists

Biophys J. 2001 May;80(5):2152-66. doi: 10.1016/S0006-3495(01)76188-7.

Abstract

Two distinct forms of desensitization have been characterized for N-methyl-D-aspartate (NMDA) receptors. One form results from a weakening of agonist affinity when channels are activated whereas the other form of desensitization results when channels enter a long-lived nonconducting state. A weakening of glycine affinity upon NMDA receptor activation has been reported. Cyclic reaction schemes for NMDA receptor activation require that a concomitant affinity shift should be observed for glutamate agonists. In this study, measurements of peak and steady-state NMDA receptor currents yielded EC50 values for glutamate that differed by 1.9-fold, but no differences were found for another agonist, L-cysteine-S-sulfate (LCSS). Simulations show that shifts in EC50 values may be masked by significant degrees of desensitization resulting from channels entering a long-lived nonconducting state. Simulations also show that a decrease in the degree of desensitization with increasing agonist concentration is a good indicator for the existence of desensitization resulting from a weakening of agonist affinity. Both glutamate and LCSS exhibited this trend. An affinity difference of three- to eightfold between high-and low-affinity agonist-binding states was estimated from fitting of dose-response data with models containing both types of desensitization. This indicates that activation of NMDA receptors causes a reduction in both glutamate and glycine affinities.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Animals, Newborn
  • Cells, Cultured
  • Cysteine / analogs & derivatives
  • Cysteine / pharmacology
  • Dose-Response Relationship, Drug
  • Glutamates / chemistry*
  • Glutamates / metabolism
  • Glycine / chemistry
  • Kinetics
  • Models, Chemical
  • Neurons / metabolism
  • Patch-Clamp Techniques
  • Perfusion
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / chemistry*

Substances

  • Glutamates
  • Receptors, N-Methyl-D-Aspartate
  • S-sulphocysteine
  • Cysteine
  • Glycine