Abstract
Oligoprenyl phosphates are key metabolic intermediates for the biosynthesis of steroids, the side chain of ubiquinones, and dolichols and the posttranslational isoprenylation of proteins. Farnesyl phosphates are isoprenoid phosphates that resemble polyunsaturated fatty alcohol phosphates, which we have recently shown to be the minimal pharmacophores of lysophosphatidic acid (LPA) receptors. Here we examine whether farnesyl phosphates can interact with the cell surface and nuclear receptors for LPA. Both farnesyl phosphate and farnesyl diphosphate potently and specifically antagonized LPA-elicited intracellular Ca(2+)-mobilization mediated through the LPA(3) receptor, while causing only modest inhibition at the LPA(2) receptor and no measurable effect at the LPA(1) receptor. Farnesol also inhibited LPA(3) but was much less effective. The estimated dissociation constant of LPA(3) for farnesyl phosphate is 48+/-12 nM and 155+/-30 nM for farnesyl diphosphate. The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) binds to and is activated by LPA and its analogs including fatty alcohol phosphates. We found that both farnesyl phosphate and diphosphate, but not farnesol, compete with the binding of the synthetic PPARgamma agonist [(3)H]rosiglitazone and activate the PPARgamma-mediated gene transcription. Farnesyl monophosphate at 1 microM, but not diphosphate, activated PPARalpha and PPARbeta/delta reporter gene expression. These results indicate new potential roles for the oligoprenyl phosphates as potential endogenous modulators of LPA targets and show that the polyisoprenoid chain is recognized by some LPA receptors.