Larixol is not an inhibitor of Gαicontaining G proteins and lacks effect on signaling mediated by human neutrophil expressed formyl peptide receptors

Abstract

AbstractNeutrophils express several G protein-coupled receptors (GPCRs) connected to intracellular Gαior Gαqcontaining G proteins for down-stream signaling. To dampen GPCR mediated inflammatory processes, several inhibitors targeting the receptors and/or their down-stream signals, have been developed. Potent and selective inhibitors for Gαqcontaining G proteins are available, but potent and specific inhibitors of Gαicontaining G proteins are lacking. Recently, Larixol, a compound extracted from the root ofEuphorbia formosana, was shown to abolish human neutrophil functions induced byN-formyl-methionyl-leucyl-phenylalanine (fMLF), an agonist recognized by formyl peptide receptor 1 (FPR1) which couple to Gαicontaining G proteins. The inhibitory effect was suggested to be due to interference with/inhibition of signals transmitted by βγ complexes of the Gαicontaining G proteins coupled to FPR1. In this study, we applied Larixol, obtained from two different commercial sources, to determine the receptor- and G protein-selectivity of this compound in human neutrophils. However, our data show that Larixol not only lacks inhibitory effect on neutrophil responses mediated through FPR1, but also on responses mediated through FPR2, a Gαicoupled GPCR closely related to FPR1. Furthermore, Larixol did not display any features as a selective inhibitor of neutrophil responses mediated through the Gαqcoupled GPCRs for platelet activating factor and ATP. Hence, our results imply that the inhibitory effects described for the root extract ofEuphorbia formosanaare not mediated by Larixol and that the search for a selective inhibitor of G protein dependent signals generated by Gαicoupled neutrophil GPCRs must continue.