Abstract
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, andXenopus 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.
Footnotes
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↵1 Current address: Serono Laboratories, Randolph, MA.
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This work was supported by grants from the National Institutes of Health (USPHS HL07641 and GM43880), from the American Heart Association, by grants from the National Science Foundation (IBN 9728147), and by the University of Memphis.
- Abbreviations:
- LPA
- lysophosphatidic acid
- S1P
- sphingosine-1-phosphate
- PLGF
- phospholipid growth factor
- EDG
- endothelial differentiation gene
- DGPP
- diacylglycerol pyrophosphate
- PA
- phosphatidic acid
- FBS
- fetal bovine serum
- DMEM
- Dulbecco's modified Eagle's medium
- RT-PCR
- reverse transcription-polymerase chain reaction
- DAG
- diacylglycerol
- Received February 9, 2001.
- Accepted June 28, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
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