LPA4/p2y9/GPR23 Mediates Rho-dependent Morphological Changes in a Rat Neuronal Cell Line

Lysophosphatidic acid (LPA) is a potent lipid mediator that evokes a variety of biological responses in many cell types via its specific G protein-coupled receptors. In particular, LPA affects cell morphology, cell survival, and cell cycle progression in neuronal cells. Recently, we identified p2y9/GPR23 as a novel fourth LPA receptor, LPA4 (Noguchi, K., Ishii, S., and Shimizu, T. (2003) J. Biol. Chem. 278, 25600-25606). To assess the functions of LPA4 in neuronal cells, we used rat neuroblastoma B103 cells that lack endogenous responses to LPA. In B103 cells stably expressing LPA4, we observed Gq/11-dependent calcium mobilization, but LPA did not affect adenylyl cyclase activity. In LPA4 transfectants, LPA induced dramatic morphological changes, i.e. neurite retraction, cell aggregation, and cadherin-dependent cell adhesion, which involved Rho-mediated signaling pathways. Thus, our results demonstrated that LPA4 as well as LPA1 couple to Gq/11 and G12/13, whereas LPA4 differs from LPA1 in that it does not couple to Gi/o. Through neurite retraction and cell aggregation, LPA4 may play a role in neuronal development such as neurogenesis and neuronal migration.