A POSSIBLE ROLE OF GLUTATHIONE AS AN ENDOGENOUS AGONIST AT THE N-METHYL-D-ASPARTATE RECOGNITION DOMAIN IN RAT-BRAIN

Glutathione, both reduced (GSH) and oxidized (GSSG), was effective in displacing binding of L-[H-3]glutamic acid (L-[H-3]GlU) and -(E)-2-[H- 3]amino-4-propyl-5-phosphono-3-pentenoic acid ([H-3]CGP-39653) in rat brain synaptic membranes, with less potent displacement of binding of amino-3-hydroxy-5-[H-3]methylisoxazole-4-propionic and [H-3] kainic ac ids. Liquid chromatographic analysis revealed that both GSH and GSSG w ere contaminated with L-Glu by <1%. Both GSH and GSSG potentiated (+)- 5-[H-3]methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine ([ H-3]MK-801) binding in a manner similar to that found with L-Glu. Pret reatment with glutamate dehydrogenase (GDH) induced a marked rightward shift of the concentration-response curve for L-Glu in the presence o f NAD without affecting that in its absence, whereas GDH was ineffecti ve in affecting the potentiation by both GSH and GSSG even in the pres ence of NAD. In the presence of GSH at a maximally effective concentra tion, both glycine (Gly) and spermidine potentiated [H-3]MK-801 bindin g to a somewhat smaller extent than that found in the presence of L-Gl u at a maximally effective concentration. The potentiation of [H-3]MK- 801 binding by GSH was invariably attenuated by addition of CGP-39653, D-2-amino-5-phosphonovaleric acid (D-AP5), and 5,7-dichlorokynurenic acid (DCKA), whereas GSH was effective in diminishing potencies of CGP -39653, D-AP5, DCKA, and 6,7-dichloroquinoxaline-2,3-dione to inhibit [H-3]MK-801 binding when determined in the presence of both L-Glu and Gly. These results suggest that glutathione may be an endogenous agoni st selective for the N-methyl-D-aspartate (NMDA) recognition domain on the NMDA receptor ionophore complex.