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J. Biol. Chem., Vol. 282, Issue 7, 4310-4317, February 16, 2007

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LPA₄/GPR23 Is a Lysophosphatidic Acid (LPA) Receptor Utilizing G_s-, G_q/G_i-mediated Calcium Signaling and G12/13-mediated Rho Activation^*

From the Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California 92037

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 LPA₄-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; G_12/13- and Rho-mediated neurite retraction and stress fiber formation; G_q protein and pertussis toxin-sensitive calcium mobilization and activation of a nonselective cation conductance; and cAMP increases mediated by G_s. 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.

Received for publication, November 22, 2006

^* This work was supported by National Institute of Mental Health Grants K02-MH01723 and R01-MH51699 and NINDS Grant R01-NS048478 and NICHD Grant R01-050685 from the National Institutes of Health (to J. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., ICND-118, La Jolla, CA 92037. Tel.: 858-784-8410; Fax: 858-784-7084; E-mail: jchun{at}scripps.edu.

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