Modification of Brain Guanine Nucleotide‐Binding Regulatory Proteins by Tryptamine‐4,5‐Dione, a Neurotoxic Derivative of Serotonin

Abstract: 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 [³H]tryptamine‐4,5‐dione resulted in the radiolabeling of a major band with an apparent molecular mass equivalent to that of the α subunits of G_i and G_o (∼40,000). The binding of [³⁵S]guanosine‐5′‐O‐(3‐thiotriphosphate) ([³⁵S]GTP‐γ‐S) to G_i and G_o and pertussis toxin‐catalyzed [³²P]ADP‐ribosylation of the G protein α 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.