ON THE MECHANISM OF THE INHIBITION OF TRANSDUCIN FUNCTION BY FARNESYLCYSTEINE ANALOGS

The gamma subunits of heterotrimeric G proteins are isoprenylated/meth ylated on their carboxy termini. The photoreceptor G protein, transduc in, is farnesylated/methylated at this position. Since the isoprenyl g roup is required for G protein function, it is of great interest to de termine the mechanism by which the farnesyl group of T gamma interacts with the other transducin subunits and/or the activated photoreceptor , rhodopsin. Farnesylcysteine derivatives (N-acetyl-S-farnesyl-L-cyste ine and farnesylated peptides) have been previously shown to have effe cts on transducin activity at high concentrations. Here, an extensive survey is done of farnesylcysteine analogs and other lipid molecules, which are tested for their ability to inhibit GTP/GDP exchange in tran sducin catalyzed by photolyzed rhodopsin. These studies are carried ou t to determine the nature of the inhibition process. While it does not appear that these molecules exhibit the specificity which would chara cterize a ligand-receptor type mechanism, the results suggest that the se compounds are not acting in a nonspecific detergent-like manner eit her. The most likely mode of action of farnesylcysteine analogs is tha t they interfere with the lipid-lipid based association of T alpha and T beta gamma through the lipid modifications present on each subunit.