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J. Biol. Chem., Vol. 283, Issue 34, 23429-23439, August 22, 2008

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Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII^*

Lily I. Jiang¹, Julie Collins, Richard Davis, Iain D. Fraser, and Paul C. Sternweis²

From the Alliance for Cellular Signaling, Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390 and the Division of Biology, Caltech, Pasadena, California 91125

Regulation of intracellular cAMP by multiple pathways enables differential function of this ubiquitous second messenger in a context-dependent manner. Modulation of G_s-stimulated intracellular cAMP has long been known to be modulated by the G_i and G_q/Ca²⁺ pathways. Recently, the G₁₃ pathway was also shown to facilitate cAMP responses in murine macrophage cells. We report here that this synergistic regulation of cAMP synthesis by the G_s and G₁₃ pathways is mediated by a specific isoform of adenylyl cyclase, AC7. Furthermore, this signaling paradigm exists in several hematopoietic lineages and can be recapitulated by exogenous expression of AC7 in HEK 293 cells. Mechanistic characterization of this synergistic interaction indicates that it occurs downstream of receptor activation and it can be mediated by the subunit of either G₁₂ or G₁₃. Our results demonstrate that AC7 is a specific downstream effector of the G_12/13 pathway.

Received for publication, April 29, 2008 , and in revised form, June 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants GM62114 and GM31954 (to P. C. S.). This work was also supported by grants from 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 Figs. S1-S5.

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

² To whom correspondence may be addressed: 5323 Harry Hines Blvd., Dallas, TX 75390. Tel.: 214-645-6149; Fax: 214-645-6151; E-mail: paul.sternweis{at}utsouthwestern.edu.

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