MODIFICATION OF BRAIN GUANINE NUCLEOTIDE-BINDING REGULATORY PROTEINS BY TRYPTAMINE-4,5-DIONE, A NEUROTOXIC DERIVATIVE OF SEROTONIN

We have recently characterized a novel oxidation product of serotonin (5-hydroxytryptamine, 5-HT), tryptamine-4,5-dione, which increases 5-HT efflux from striatum and hippocampus and causes selective neuronal death. Exposure of striatal synaptosomes or the major brain guanine nucleotide-binding regulatory proteins G(i) and G(o) to [H-3]tryptamine-4,5-dione resulted in the radiolabeling of a major band with an apparent molecular mass equivalent to that of the alpha subunits of G(i) and G(o) (approximately 40,000). The binding of [S-35]guanosine-5'-O-(3-thiotriphosphate) ([S-35]GTP-gamma-S) to G(i) and G(o) and pertussis toxin-catalyzed [P-32]ADP-ribosylation of the G protein alpha subunits were both inhibited in a dose-dependent manner by tryptamine-4,5-dione. Thus, neurotoxins such as tryptamine-4,5-dione may exert their effects through specific interactions with G proteins.