Alteration of the NMDA associated ion channel binding sites in the epileptic mutant mouse quaking

Abstract

Two competitive (CPP and CGS 19755) and two non-competitive (TCP and MK-801) antagonists of the NMDA receptor/ion channel complex inhibited in a dose dependent manner the convulsions of the quaking mice, a model of inherited epilepsy. However, the effects of the competitive antagonists (which bind to the NMDA recognition site) were not complete, and were accompanied by a marked ataxia, while the noncompetitive antagonists (which interact with the NMDA-receptor associated ion channel) fully protected the quaking mice and did not induce any noticeable side effect. The binding of 3H-glutamate to thoroughly washed brain membranes did not show any difference between the mutants and their controls. Moreover, CPP and CGS 19755 appeared equally potent at displacing the binding of 3H-glutamate in the two strains. The binding of 3H-TCP appeared to be markedly higher in the quaking mice than in the controls (Bmax qk: 3.11 ± 0.47 pmol/mg prot, n=5; controls: 1.80 ± 0.18 pmol/mg prot, n=6), without any change of the affinity constant (Kd qk: 70.8 ± 14.4 nM, n=5; controls: 54.3 ± 3.6 nM, n=6). In both quaking and control mice, 3H-TCP binding could be modulated by glutamate and glycine. In addition, the ability of glutamate and glutamate + glycine to enhance the binding of 3H-TCP was higher in the mutants than in the controls.