Naturally occurring analogs of lysophosphatidic acid elicit different cellular responses through selective activation of multiple receptor subtypes

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 act ivation of G protein-coupled receptors in a variety of cell types. In NIH3T 3 fibroblasts, LPA and alkenyl-GP both induced proliferation, whereas cycli c-PA was antiproliferative. LPA and alkenyl-GP decreased cAMP in a pertussi s toxin-sensitive manner, whereas cyclic-PA caused cAMP to increase. LPA an d alkenyl-GP both stimulated the activity of the mitogen-actived protein ki nases extracellular signal regulated kinases 1 and 2 and c-Jun NH2-terminal kinase, whereas cyclic-PA did not. All three PLGFs induced the formation o f stress fibers in NIH3T3 fibroblasts. To determine whether these lipids ac tivated the same or different receptors, heterologous desensitization patte rns were established among the three PLGFs by monitoring changes in intrace llular Ca2+ in NIH3T3 fibroblasts. LPA cross-desensitized both the alkenyl- GP and cyclic-PA responses. Alkenyl-GP cross-desensitized the cyclic-PA res ponse, but only partially desensitized the LPA response. Cyclic-PA only par tially 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-exp ression of mRNAs encoding the EDGE, 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 t hat a number of PLGF receptor subtypes remain unidentified.