Epac

Epac, short for Exchange Protein directly Activated by cAMP, is a family of intracellular signaling proteins that function as guanine nucleotide exchange factors for the small GTPases Rap1 and Rap2. Epac proteins are directly activated by cyclic AMP (cAMP) and operate independently of the classic cAMP effector protein kinase A (PKA). In humans, the two main isoforms are EPAC1 (encoded by RAPGEF3) and EPAC2 (encoded by RAPGEF4). EPAC1 is expressed broadly, whereas EPAC2 is enriched in the brain and in several peripheral tissues such as the pancreas and adrenal glands; multiple tissue-specific isoforms arise from alternative splicing of these genes.

Structure: EPAC proteins possess an N-terminal regulatory region containing cyclic nucleotide-binding (CNB) domains and a Dishevelled/Egl-10/Pleckstrin (DEP) domain that aids membrane localization, followed by a catalytic CDC25-homology GEF domain responsible for activating Rap1 and Rap2 by promoting GDP-GTP exchange.

Activation mechanism: binding of cAMP to the CNB domains relieves an autoinhibitory interaction, enabling the CDC25-homology domain to catalyze nucleotide exchange on Rap1/2. Active Rap1 then signals through multiple effectors to regulate processes such as cell adhesion, cytoskeletal organization, and vesicle exocytosis.

Physiological roles: EPAC signaling contributes to insulin secretion in pancreatic beta cells, regulation of neuronal plasticity and neurite outgrowth, and control of endothelial barrier function and vascular integrity. In cancer cells, Epac–Rap signaling influences adhesion and migration in a context-dependent manner.

Research tools and pharmacology: cAMP analogs that selectively activate Epac, such as 8-pCPT-2'-O-Me-cAMP and cell-permeable derivatives, are widely used to dissect Epac-specific pathways. Small-molecule inhibitors of Epac are used to suppress Epac signaling in experimental systems.

History: Epac was identified in the late 1990s as a direct cAMP-binding GEF for Rap proteins, providing a distinct branch of cAMP signaling separate from PKA.