Lysophosphatidic acid (LPA) is a potent lipid mediator with diverse physiological actions on a wide variety of cells and tissues. Three cognate G-protein-coupled receptors have been identified as mammalian LPA receptors: LP(A)1/VZG-1/EDG-2, LP(A)2/EDG-4, and LP(A)3/EDG-7. The mouse forms of these genes were analyzed in rodent cell lines derived from nervous system cells that can express these receptors functionally. An efficient retrovirus expression system was used, and each receptor was heterologously expressed in B103 rat neuroblastoma cells that neither express these receptors nor respond to LPA in all assays tested. Comparative analyses of signaling pathways that are activated within minutes of ligand delivery were carried out. LPA induced cell rounding in LP(A)1- and LP(A)2-expressing cells. By contrast, LP(A)3 expression resulted in neurite elongation in B103 cells and inhibited LPA-dependent cell rounding in TR mouse neuroblast cells that endogenously express LP(A1) and LP(A2) but not LP(A3). Each of the receptors could couple to multiple G-proteins and induced LPA-dependent inositol phosphate production, mitogen-activated protein kinase activation, and arachidonic acid release while inhibiting forskolin-induced cAMP accumulation, although the efficacy and potency of LPA varied from receptor to receptor. These results indicate both shared and distinct functions among the three mammalian LPA receptors. The retroviruses developed in this study should provide tools for addressing these functions in vivo.
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