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Vol. 60, Issue 4, 776-784, October 2001
Department of Physiology, University of Tennessee Health Science
Center, Memphis, Tennessee (D.J.F., N.N., T.V., K.Y., D.W.,
D.L.B., G.T.); and Department of Chemistry and Computational Research
on Materials Institute, University of Memphis, Memphis, Tennessee
(D.B., A.L.P.)
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
LPA1 and LPA3 receptors, but prefer
LPA3 by an order of magnitude. Neither molecule had an
agonistic or antagonistic effect on LPA2 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 S1P1,
S1P2, S1P3, and S1P5 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.
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