Regulation of cAMP responses by the G12/13 pathway converges on adenylyl cyclase VII
Abstract
Regulation of intracellular cyclic adenosine 3', 5'-monophosphate (cAMP) by multiple pathways enables differential function of this ubiquitous second messenger in a context dependent manner. Modulation of Gs-stimulated intracellular cAMP has long been known to be modulated by the Gi and Gq/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 Gs 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 alpha subunit of either G12 or G13. Our results demonstrate that AC7 is a specific downstream effector of the G12/13 pathway.
Additional Information
© 2008 the American Society for Biochemistry and Molecular Biology. Submitted on April 29, 2008. Revised on June 3, 2008. Accepted on June 9, 2008. Originally published In Press as doi:10.1074/jbc.M803281200 on June 9, 2008. We thank Dr. Tamara Roach for providing the PlatE and CMG14-12 cell lines, Dr. William Singer for the G13QL construct and G{alpha}13 antibody, and Dr. Ronald Taussig for rat AC2 and human AC7 cDNAs. We are grateful to Drs. Elliott Ross and Ronald Taussig for enlightening discussions and comments on this manuscript. 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.Attached Files
Published - JIAjbc08.pdf
Accepted Version - JIAjbc08pip.pdf
Supplemental Material - JIAjbc08supdata.pdf
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Additional details
- PMCID
- PMC2516994
- Eprint ID
- 11042
- Resolver ID
- CaltechAUTHORS:JIAjbc08
- GM62114
- NIH
- GM31954
- NIH
- Robert A. Welch Foundation
- Alfred and Mabel Gilman Chair in Molecular Pharmacology, UT Southwestern Medical Center
- Created
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2008-06-24Created from EPrint's datestamp field
- Updated
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2021-11-08Created from EPrint's last_modified field