Desensitization of NMDA receptor channels is modulated by glutamate agonists.
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.
Nahum-Levy
R
R
Department of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel.
Lipinski
D
D
Shavit
S
S
Benveniste
M
M
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005971:Glutamates / Q000737:chemistry* / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D007700:Kinetics; D008956:Models, Chemical; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010477:Perfusion; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry*
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; C011119:S-sulphocysteine; D003545:Cysteine; D005998:Glycine