The alpha subunit (G(5 alpha)) of the stimulatory heterotrimeric guanosine triphosphate binding protein (G protein) G(s) activates all isoforms of mammalian adenylyl cyclase. Adenylyl cyclase (Type V) and its subdomains, which interact with G(5 alpha), promoted inactivation of the G protein by increasing its guanosine triphosphatase (GTPase) activity. Adenylyl cyclase and its subdomains also augmented the receptor-mediated activation of heterotrimeric G, and thereby facilitated the rapid onset of signaling. These findings demonstrate that adenylyl cyclase functions as a GTPase activating protein (GAP) for the monomeric G(5 alpha) and enhances the GTP/GDP exchange factor (EF) activity of receptors.