Naturally Occurring Analogs of Lysophosphatidic Acid Elicit Different Cellular Responses through Selective Activation of Multiple Receptor Subtypes

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-Jun NH2-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.

Enhancement of survival by LPA via Erk1/Erk2 and PI 3-kinase/Akt pathways in a murine hepatocyte cell line

“…Particularly, no Edg2 mRNA was detected in liver tissue during Northern blotting (1,15,21). Our data clearly indicate the presence of a 483-bp fragment corresponding to the Edg2 receptor in RT-PCR analyses of AML12 hepatocytes (Fig.…”

Molecular Cloning and Characterization of a Novel Human G-protein-coupled Receptor, EDG7, for Lysophosphatidic Acid

“…In fact, LPA inhibited adenylyl cyclase in EDG2-transfected mammalian cells (9). On the other hand, in nonfibroblastic cell line Sp2/0-Ag14 myeloma, which does not express either EDG2 or EDG4 (22), LPA induced an increase in cAMP and inhibited cell proliferation in a PTXinsensitive manner, which is accompanied by an increase in cytoplasmic Ca 2ϩ (4). They also indicated that LPA with a higher degree of unsaturation and longer acyl chains increased the antiproliferative effects (4).…”

“…A novel GPCR, named PSP24, which does not show significant sequence similarity with any member of the EDG family, has also been isolated from Xenopus oocytes as a functional receptor for LPA (21). Because some LPA-responsive cells do not express known LPA receptors (EDG2, EDG4, and PSP24), it was expected that unidentified subtypes of LPA receptors were suggested to be present in mammals (11,22). To understand the biological functions of LPA fully, we attempted to identify novel subtypes of LPA receptors.…”

Role of RhoA and Rho Kinase in Lysophosphatidic Acid–Induced Endothelial Barrier Dysfunction

“…9 Prolonged exposure to LPA results in downregulation of LPA receptors. 30 Thus, it is likely that the effect of LPA on endothelial barrier function is underestimated.…”