Abstract
Lysophosphatidic acid (LPA), plasmalogen-glycerophosphate (alkenyl-GP) and, cyclic-phosphatidic acid (cyclic-PA) are naturally occurring phospholipid growth factors (PLGFs). PLGFs elicit diverse biological effects via the activation of G protein-coupled receptors in a variety of cell types. In NIH3T3 fibroblasts, LPA and alkenyl-GP both induced proliferation, whereas cyclic-PA was antiproliferative. LPA and alkenyl-GP decreased cAMP in a pertussis toxin-sensitive manner, whereas cyclic-PA caused cAMP to increase. LPA and alkenyl-GP both stimulated the activity of the mitogen-actived protein kinases extracellular signal regulated kinases 1 and 2 and c-JunNH2-terminal kinase, whereas cyclic-PA did not. All three PLGFs induced the formation of stress fibers in NIH3T3 fibroblasts. To determine whether these lipids activated the same or different receptors, heterologous desensitization patterns were established among the three PLGFs by monitoring changes in intracellular Ca2+ in NIH3T3 fibroblasts. LPA cross-desensitized both the alkenyl-GP and cyclic-PA responses. Alkenyl-GP cross-desensitized the cyclic-PA response, but only partially desensitized the LPA response. Cyclic-PA only partially desensitized both the alkenyl-GP and LPA responses. We propose that pharmacologically distinct subsets of PLGF receptors exist that distinguish between cyclic-PA and alkenyl-GP, but are all activated by LPA. We provide evidence that the PSP24 receptor is selective for LPA and not activated by the other two PLGFs. RT-PCR and Northern blot analysis indicate the co-expression of mRNAs encoding the EDG-2, EDG-4, and PSP24 receptors in a variety of cell lines and tissues. However, the lack of mRNA expression for these three receptors in the LPA-responsive Rat-1 and Sp2-O-Ag14 cells suggests that a number of PLGF receptor subtypes remain unidentified.
Footnotes
- Received July 9, 1998.
- Accepted September 2, 1998.
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Send reprint requests to: Gábor Tigyi, M.D., Ph.D., Department of Physiology and Biophysics, College of Medicine, University of Tennessee, 894 Union Avenue, Memphis, TN 38163. E-mail:gtigyi{at}physio1.utmem.edu
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This work was supported by grants from the National Science Foundation (IBN-9722969-GT), National Institutes of Health-National Heart, Lung, and Blood Institute (G.T.), LXR Biotechnology, Inc. (G.T.), The Hungarian Ministry of Culture and Education (K.M.), the Special Coordination Funds for Promoting Science and Technology from the Science and Technology Agency of Japan (S.K.). G.T. is an Established Investigator of the American Heart Association. D.J.F. is a Fellow of the American Heart Association-Tennessee Affiliate and the recipient of an National Institutes of Health Training Grant (HL07746). K.L. and G.S. are recipients of a Postdoctoral Fellowship from the Center for Neuroscience at The University of Tennessee Memphis.
- The American Society for Pharmacology and Experimental Therapeutics
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