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J. Biol. Chem., Vol. 282, Issue 14, 10576-10584, April 6, 2007

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Use of a cAMP BRET Sensor to Characterize a Novel Regulation of cAMP by the Sphingosine 1-Phosphate/G₁₃ Pathway^*

Lily I. Jiang¹, Julie Collins, Richard Davis, Keng-Mean Lin, Dianne DeCamp, Tamara Roach, Robert Hsueh, Robert A. Rebres, Elliott M. Ross, Ronald Taussig, Iain Fraser^¶, and Paul C. Sternweis²

From the Department of Pharmacology, Alliance for Cellular Signaling, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9196, the Veterans Administration Medical Center, University of California, San Francisco, California 94121, and the ^¶Division of Biology, California Institute of Technology, Pasadena, California 91125

Regulation of intracellular cyclic adenosine 3 ',5 '-monophosphate (cAMP) is integral in mediating cell growth, cell differentiation, and immune responses in hematopoietic cells. To facilitate studies of cAMP regulation we developed a BRET (bioluminescence resonance energy transfer) sensor for cAMP, CAMYEL (cAMP sensor using YFP-Epac-RLuc), which can quantitatively and rapidly monitor intracellular concentrations of cAMP in vivo. This sensor was used to characterize three distinct pathways for modulation of cAMP synthesis stimulated by presumed G_s-dependent receptors for isoproterenol and prostaglandin E₂. Whereas two ligands, uridine 5 '-diphosphate and complement C5a, appear to use known mechanisms for augmentation of cAMP via G_q/calcium and G_i, the action of sphingosine 1-phosphate (S1P) is novel. In these cells, S1P, a biologically active lysophospholipid, greatly enhances increases in intracellular cAMP triggered by the ligands for G_s-coupled receptors while having only a minimal effect by itself. The enhancement of cAMP by S1P is resistant to pertussis toxin and independent of intracellular calcium. Studies with RNAi and chemical perturbations demonstrate that the effect of S1P is mediated by the S1P₂ receptor and the heterotrimeric G₁₃ protein. Thus in these macrophage cells, all four major classes of G proteins can regulate intracellular cAMP.

Received for publication, October 16, 2006 , and in revised form, January 29, 2007.

^* This work was supported by National Institutes of Health Grant GM 62114, the Robert A. Welch foundation (to P. C. S.), and the Alfred and Mabel Gilman Chair in Molecular Pharmacology (to P. C. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and Figs. S1-S7.

¹ To whom correspondence may be addressed: UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9196. Tel.: 214-645-6105; Fax: 214-645-6118; E-mail: lily.jiang{at}utsouthwestern.edu.

² To whom correspondence may be addressed: UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9196. Tel.: 214-645-6149; Fax: 214-645-6118; E-mail: paul.sternweis{at}utsouthwestern.edu.

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