Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors.
Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are members of the phospholipid growth factor family. A major limitation in the field to date has been a lack of receptor subtype-specific agonists and antagonists. Here, we report that dioctylglycerol pyrophosphate and dioctylphosphatidic acid are selective antagonists of the LPA(1) and LPA(3) receptors, but prefer LPA(3) by an order of magnitude. Neither molecule had an agonistic or antagonistic effect on LPA(2) receptor. Consistent with this receptor subtype selectivity, dioctylglycerol pyrophosphate inhibited cellular responses to LPA in NIH3T3 fibroblasts, HEY ovarian cancer cells, PC12 pheochromocytoma cells, and Xenopus laevis oocytes. Responses elicited by S1P in these cell lines that endogenously express S1P(1), S1P(2), S1P(3), and S1P(5) receptors were unaffected by dioctylglycerol pyrophosphate. Responses evoked by the G protein-coupled receptor ligands acetylcholine, serotonin, ATP, and thrombin receptor-activating peptide were similarly unaffected, suggesting that the short-chain phosphatidates are receptor subtype-specific lysophosphatidate antagonists.
Fischer
D J
DJ
Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Nusser
N
N
Virag
T
T
Yokoyama
K
K
Wang Da
Baker
D L
DL
Bautista
D
D
Parrill
A L
AL
Tigyi
G
G
D016475:3T3 Cells; D000109:Acetylcholine / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D011756:Diphosphates / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D051379:Mice; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D051381:Rats; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D049312:Receptors, Lysophospholipid; D012701:Serotonin / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D014982:Xenopus laevis
D011756:Diphosphates; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D049312:Receptors, Lysophospholipid; C408642:diacylglycerol pyrophosphate; D012701:Serotonin; D000255:Adenosine Triphosphate; D013917:Thrombin; D000109:Acetylcholine; D005990:Glycerol; D002118:Calcium