Farnesylcysteine analogues inhibit chemotactic peptide receptor-mediated G-protein activation in human HL-60 granulocyte membranes.

Analogues of S-prenylated cysteine like N-acetyl-S-trans,trans-farnesyl-L-cysteine (AFC) have previously been shown to inhibit the carboxyl methylation of proteins carrying a C-terminal S-prenylated cysteine residue and to block the endotoxin-activated serum-elicited chemotactic response of mouse macrophages. Here, we show that AFC inhibits both basal and formyl peptide receptor-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP[S]) to and hydrolysis of GTP by membranes of myeloid differentiated HL-60 granulocytes. Receptor-stimulated GTP[S] binding and GTP hydrolysis are more sensitive to AFC inhibition than basal G-protein functions. Inhibition of formyl peptide receptor-mediated G-protein activation is also observed for S-trans,trans-farnesyl-3-thiopropionic acid, but not for N-acetyl-S-trans-geranyl-L-cysteine, N-acetyl-L-cysteine, or the methyl ester of AFC, suggesting that the farnesyl moiety and the carboxyl group, but not the peptide bond of AFC are required for inhibition. The observations that exogeneous S-adenosyl-L-methionine is apparently not required for and S-adenosyl-L-homocysteine does not attenuate the inhibitory action of AFC raise the distinct possibility that AFC inhibits receptor-mediated G-protein interaction by a mechanism other than inhibition of protein carboxyl methylation.