Regulation of cAMP responses by the G12/13 pathway converges on adenylyl cyclase VII.
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)/Ca(2+) pathways. Recently, the G(13) 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 G(13) 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 G(12) or G(13). Our results demonstrate that AC7 is a specific downstream effector of the G(12/13) pathway.
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. lily.jiang@utsouthwestern.edu
Lily I
LI
Jiang
Julie
J
Collins
Richard
R
Davis
Iain D
ID
Fraser
Paul C
PC
Sternweis
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010641:Phenotype; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors
D000242:Cyclic AMP; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D000262:Adenylyl Cyclases; C473265:adenylyl cyclase 7