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Vol. 58, Issue 5, 895-902, November 2000
Department of Pharmacology (I.I., J.J.A.C., N.F., J.C.) and
Neurosciences and Biomedical Sciences Programs (J.C.), School of
Medicine, University of California, San Diego, La Jolla, California
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: LPA1/VZG-1/EDG-2, LPA2/EDG-4,
and LPA3/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
LPA1- and LPA2-expressing cells. By contrast,
LPA3 expression resulted in neurite elongation in B103
cells and inhibited LPA-dependent cell rounding in TR mouse neuroblast
cells that endogenously express LPA1 and LPA2
but not LPA3. 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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