Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1761, Issue 12, Pages 1506-1514Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2006.09.012
Keywords
farnesyl phosphate; isoprenoid; LPA; lysophospholipid; GPCR; PPAR gamma
Funding
- NCI NIH HHS [R01 CA092160] Funding Source: Medline
- NHLBI NIH HHS [R01 HL061469, R01 HL079004, HL79004, HL61469] Funding Source: Medline
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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 Ca2+-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. Famesol 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 (PPAR-gamma) 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 PPAR gamma agonist [H-3] rosiglitazone and activate the PPAR gamma-mediated gene transcription. Farnesyl monophosphate at 1 mu M, but not diphosphate, activated PPAR alpha and PPAR beta/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. (c) 2006 Elsevier B.V. All rights reserved.
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