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J. Biol. Chem., Vol. 282, Issue 29, 21529-21541, July 20, 2007

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Lysophosphatidic Acid Regulates Trafficking of ₂-Adrenergic Receptors

THE G₁₃/p115RhoGEF/JNK PATHWAY STIMULATES RECEPTOR INTERNALIZATION^*

Elena Shumay¹, Jiangchuan Tao¹, Hsien-yu Wang, and Craig C. Malbon²

From the Departments of Pharmacology and Physiology and Biophysics, Diabetes and Metabolic Diseases Research Program, School of Medicine, State University of New York, Stony Brook, New York 11794-8661

Lysophosphatidic acid is an important lipid ligand regulating many aspects of cell function, including proliferation and migration. Operating via heterotrimeric G proteins to downstream effectors, lysophosphatidic acid was shown to regulate the function and trafficking of the G protein-coupled ₂-adrenergic receptor. C3 exotoxin, expression of dominant negative RhoA, and inhibition of c-Jun N-terminal kinase blocked the ability of lysophosphatidic acid to sequester the ₂-adrenergic receptor, whereas expression of constitutively active G₁₃, p115RhoGEF, or RhoA mimicked lysophosphatidic acid (LPA) action, stimulating the internalization of the G_s-coupled ₂-adrenergic receptor. This study revealed a novel cross-talk exerted from the LPA/G₁₃/p115RhoGEF/RhoA pathway to the ₂-adrenergic receptor/G_s/adenylyl cyclase pathway, attenuating the ability of -adrenergic agonists to act following stimulation of cells by LPA as may occur during -adrenergic therapy of an inflammatory response.

Received for publication, March 7, 2007 , and in revised form, May 9, 2007.

^* This work was supported by United States Public Health Service Grant DK42510 from NIDDK, National Institutes of Health (to C. C. M.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Pharmacology-HSC, State University of New York, Stony Brook, NY 11794-8651. Tel.: 631-444-7873; Fax: 631-444-7696; E-mail craig{at}pharm.sunysb.edu.

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