EPACdependent

Epac-dependent refers to cellular signaling pathways that rely on Epac proteins as the effector of cyclic AMP (cAMP) signaling, in contrast to pathways mediated by protein kinase A (PKA). Epac stands for Exchange Protein directly Activated by cAMP and denotes a family of cAMP-binding guanine nucleotide exchange factors for the Rap family of small GTPases.

In mammals, two isoforms, Epac1 (Rapgef3) and Epac2 (Rapgef4), are encoded by distinct genes and have overlapping but tissue-specific expression patterns: Epac1 is widely expressed in many tissues, while Epac2 is enriched in brain and pancreatic islets.

Activation occurs when cAMP binds to the regulatory cAMP-binding domains (CNBDs) of Epac, relieving autoinhibitory constraints and promoting the catalytic CDC25 homology domain to activate Rap1 and Rap2 by promoting GDP-GTP exchange. Activated Rap1/2 regulate processes such as cell adhesion, integrin signaling, exocytosis, cytoskeletal remodeling, and barrier function.

Epac-dependent signaling modulates insulin secretion in pancreatic beta cells, neurotransmitter release and synaptic plasticity in neurons, and cardiac and vascular functions. It also participates in inflammatory responses and cancer cell migration in some contexts.

Because Epac mediates cAMP effects independent of PKA, pharmacological and genetic tools that selectively activate or inhibit Epac have been developed to dissect Epac-dependent pathways. Common Epac activators include 8-pCPT-2'-O-Me-cAMP, while inhibitors such as ESI-09 have been used to suppress Epac signaling in experiments.

Understanding Epac-dependent signaling is important for appreciating diverse roles of cAMP in physiology and its potential as a therapeutic target in metabolic, cardiovascular, and neurological disorders.