LPA4/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing Gs-, Gq/Gi-mediated calcium signaling and G12/13-mediated Rho activation

Abstract

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that signals through G protein-coupled receptors (GPCRs) to produce a range of biological responses. A recently reported fourth receptor, LPA4/GPR23, was notable for its low homology to the previously identified receptors LPA 1-3 and for its ability to increase intracellular concentrations of cAMP and calcium. However, the signaling pathways leading to LPA 4-mediated induction of cAMP and calcium levels have not been reported. Using epitope-tagged LPA4, pharmacological intervention, and G protein mini-genes, we provide independent confirmatory evidence that supports LPA4 as a fourth LPA receptor, including LPA concentration-dependent responses and specific membrane binding. Importantly, we further demonstrate new LPA-dependent activities of LPA4 that include the following: receptor internalization;G12/13- and Rho-mediated neurite retraction and stress fiber formation; Gq protein and pertussis toxin-sensitive calcium mobilization and activation of a nonselective cation conductance; and cAMP increases mediated by Gs. The receptor is broadly expressed in embryonic tissues, including brain, as determined by Northern blot and reverse transcription-PCR analysis. Adult tissues have increased expression in skin, heart, and to a lesser extent, thymus. These data confirm the identification and extend the functionality of LPA4 as an LPA receptor, bringing the number of independently verified LPA receptors to five, with both overlapping and distinct signaling properties and tissue expression. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.