title: S-prenylated cysteine analogues inhibit receptor-mediated G protein activation in native human granulocyte and reconstituted bovine retinal rod outer segment membranes.
abstract: We have previously shown that the S-prenylated cysteine analogue N-acetyl-S-trans,trans-farnesyl-L-cysteine (L-AFC) inhibits basal and formyl peptide receptor-stimulated binding of guanosine 5'-O-(3-thiotriphosphate) (GTP[S]) to and hydrolysis of GTP by membranes of HL-60 granulocytes and have presented evidence suggesting that this inhibition was not caused by reduced protein carboxyl methylation [Scheer, A., & Gierschik, P. (1993) FEBS Lett. 319, 110-114]. We now report a detailed analysis of the structural properties of S-prenylated cysteine analogues required for this inhibition and demonstrate that S-prenylcysteines also suppress basal and receptor-stimulated GTP[S] binding to human peripheral neutrophil and HL-60 granulocyte membranes when stimulated by formyl peptide and complement C5a, respectively. S-Prenylcysteines did not affect pertussis toxin-mediated [32P]ADP-ribosylation of Gi proteins. The inhibitory effect of L-AFC was reversible and was not mimicked by farnesylic acid. L-AFC also interfered with GTP[S] binding to retinal transducin when stimulated by light-activated rhodopsin in a reconstituted system. This inhibitory effect was fully reversed upon increasing the concentration of either the G protein beta gamma dimer or the activated receptor. On the basis of these results, we suggest that S-prenylated cysteine analogues like L-AFC inhibit receptor-mediated G protein activation by specifically and reversibly interfering with the interaction of activated receptors with G proteins, most likely with their beta gamma dimers, rather than by inhibiting alpha.beta gamma heterotrimer formation.
authors.affiliation: German Cancer Research Center, Heidelberg.
authors.forename: A
authors.initials: A
authors.lastname: Scheer
authors.forename: P
authors.initials: P
authors.lastname: Gierschik
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000502:physiology*; D018000:Receptors, Peptide / Q000502:physiology*; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D018000:Receptors, Peptide; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D019204:GTP-Binding Proteins; D003545:Cysteine; C068268:N-acetyl-S-farnesylcysteine; D000111:Acetylcysteine