Schematic representation of domain structure and genomic organization of Epac protein isoforms. Epac1 and Epac2 consist of the N-terminal regulatory region and the C-terminal catalytic region in common, which are composed of functional multi-domains. The regulatory region contains a cyclic nucleotide-binding (CNB) domain and a dishevelled, Egl-10, Pleckstrin (DEP) domain. The CNB domain of Epac1 and CNB-B domain of Epac2 bind cAMP with a high affinity leading to Epac protein activation. The extra CNB-A domain of Epac2A1 and Epac2A2 bind cAMP with a relatively low affinity compared with the conserved CNB-B domain and is not involved in activation of Epac2. The Dishevelled, Egl-10, Pleckstrin (DEP) domain has a role in the subcellular localization of Epac protein. In the catalytic region, a RAS exchange motif (REM) domain interacting with the guanine nucleotide exchange factor (GEF) region stabilizes a GEF for Ras-like small GTPases (RasGEF) domain which is responsible for biological function of Epac protein. The RAS-association (RA) domain regulates perinuclear localization of Epac1 and plasma membrane localization of Epac2.