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.