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J. Biol. Chem., Vol. 281, Issue 33, 23589-23597, August 18, 2006

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GPR92 as a New G12/13- and G_q-coupled Lysophosphatidic Acid Receptor That Increases cAMP, LPA₅^*

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

The signaling effects of lysophospholipids such as lysophosphatidic acid (LPA) are mediated by G protein-coupled receptors (GPCRs). There are currently four LPA receptors known as LPA_1–4. Genetic deletion studies have identified essential biological functions for LPA receptors in mice. However, these studies have also revealed phenotypes consistent with the existence of as yet unidentified receptors. Toward identifying new LPA receptors, we have screened collections of GPCR cDNAs using reverse transfection and cell-based assays. Here we report an interim result of one screen to identify receptors that produced LPA-dependent changes in cell shape: the orphan receptor GPR92 has properties of a new LPA receptor. Sequence analyses of human GPR92 and its mouse homolog have 35% amino acid identity with LPA₄/GPR23. The same cell-based approaches that were used to identify and/or characterize LPA_1–4, particularly heterologous expression in B103 cells or RH7777 cells, were utilized and compared with known LPA receptors. Retroviral-mediated expression of epitope-tagged receptors was further combined with G protein minigenes and pharmacological intervention, along with calcium imaging and whole-cell patch clamp electrophysiology. LPA-dependent receptor internalization following exposure to LPA but not related lysophospholipids was observed. Furthermore, LPA induced concentration-dependent activation of G_12/13 and G_q and increased cAMP levels. Specific [³H]LPA binding was detected in cell membranes heterologously expressing GPR92 but not control membranes. Northern blot and reverse transcriptase-PCR studies indicated a broad low level of expression in many tissues including embryonic brain and enrichment in small intestine and sensory dorsal root ganglia, as well as embryonic stem cells. These results support GPR92 as a fifth LPA receptor, LPA₅, which likely has distinct physiological functions in view of its expression pattern.

Received for publication, April 17, 2006 , and in revised form, June 13, 2006.

Addendum—During review of this manuscript, Kotarsky et al. (Kotarsky, K., Boketoft, A., Bristulf, J., Nilsson, N. E., Norberg, A., Hansson, S., Sillard, R., Owman, C., Leeb-Lundberg, F. L., and Olde, B. (2006) J. Pharmacol. Exp. Ther. 318, 619–628) reported that GPR92 functions as an LPA receptor.

^* This work was supported by National Institutes of Health Grants MH51699 and NS048478 (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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