CAP1 binds and activates adenylyl cyclase in mammalian cells

Significance cAMP is a second messenger present in most cells, synthesized by adenylyl cyclase. Different isoforms are present in eukaryotes with distinct modes of regulation. In yeast, cyclase is regulated by Ras2 in a CAP1-dependent manner. CAP1 is conserved in mammals; however, its cyclase regulatory component is considered to be lost during evolution. We show that CAP1 binds and activates mammalian cyclase and reveal a role for Rap1, a CAP1 partner, in cyclase regulation in mammalian cells. These findings indicate that Rap1 is not just a downstream cAMP player but in the context of CAP1 is able to modulate cAMP synthesis, establishing a positive feedback that might provide mechanistic clues into the spatiotemporal regulation of G s -dependent cAMP signaling.