کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
1950151 1537815 2006 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: Inhibition of LPA GPCR and activation of PPARs
موضوعات مرتبط
علوم زیستی و بیوفناوری بیوشیمی، ژنتیک و زیست شناسی مولکولی زیست شیمی
پیش نمایش صفحه اول مقاله
Farnesyl phosphates are endogenous ligands of lysophosphatidic acid receptors: Inhibition of LPA GPCR and activation of PPARs
چکیده انگلیسی

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 LPA3 receptor, while causing only modest inhibition at the LPA2 receptor and no measurable effect at the LPA1 receptor. Farnesol also inhibited LPA3 but was much less effective. The estimated dissociation constant of LPA3 for farnesyl phosphate is 48 ± 12 nM and 155 ± 30 nM for farnesyl diphosphate. The transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) 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 PPARγ agonist [3H]rosiglitazone and activate the PPARγ-mediated gene transcription. Farnesyl monophosphate at 1 μM, but not diphosphate, activated PPARα and PPARβ/δ 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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids - Volume 1761, Issue 12, December 2006, Pages 1506–1514
نویسندگان
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