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-[3H]-glutamic acid (L-[3H]Glu) and DL-(E)-2-[3H]amino-4-propyl-5-phosphono-3- pentenoic acid ([3H]CGP-39653) in rat brain synaptic membranes, with less potent displacement of binding of DL-alpha-amino-3-hydroxy-5-[3H]-methylisoxazole-4-propionic and [3H]kainic acids. Liquid chromatographic analysis revealed that both GSH and GSSG were contaminated with L-Glu by < 1%. Both GSH and GSSG potentiated (+)-5-[3H]methyl-10,11-dihydro-5H-dibenzo[a, d]cyclohepten-5,10-imine ([3H]MK-801) binding in a manner similar to that found with L-Glu. Pretreatment with glutamate dehydrogenase (GDH) induced a marked rightward shift of the concentration-response curve for L-Glu in the presence of NAD without affecting that in its absence, whereas GDH was ineffective in affecting the potentiation by both GSH and GSSG even in the presence of NAD. In the presence of GSH at a maximally effective concentration, both glycine (Gly) and spermidine potentiated [3H]MK-801 binding to a some-what smaller extent than that found in the presence of L-Glu at a maximally effective concentration. The potentiation of [3H]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 [3H]MK-801 binding when determined in the presence of both L-Glu and Gly.(ABSTRACT TRUNCATED AT 250 WORDS)
Ogita
K
K
Department of Pharmacology, Setsunan University, Osaka, Japan.
Enomoto
R
R
Nakahara
F
F
Ishitsubo
N
N
Yoneda
Y
Y
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D016291:Dizocilpine Maleate / Q000378:metabolism; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D005978:Glutathione / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000502:physiology
D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; C069052:CGP 39653; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; D005969:Glutamate Dehydrogenase; D005978:Glutathione