EPAC2

EPAC2, or Exchange Protein directly Activated by cAMP 2, is a member of the RapGEF family of guanine nucleotide exchange factors. In humans it is encoded by the RAPGEF4 gene. EPAC2 acts as a GEF for the small GTPases Rap1 and Rap2 and is directly activated by cyclic AMP in a pathway that operates independently of protein kinase A (PKA). Expression is highest in the brain, particularly in the cortex and hippocampus, with additional expression in pancreatic islets, pituitary, adrenal tissues, and various peripheral cells.

EPAC2 proteins contain an N-terminal regulatory region that includes a Dishevelled-Egl-10-Pleckstrin (DEP) domain and a cAMP-binding regulatory region with a cyclic nucleotide-binding domain, followed by a CDC25 homology catalytic domain responsible for RAPGEF activity. Alternative splicing generates multiple EPAC2 isoforms with tissue-specific patterns; some isoforms differ in domain composition and subcellular targeting.

Binding of cAMP to the CNBD relieves autoinhibition and activates the CDC25 domain, promoting GDP-to-GTP exchange on Rap1 and Rap2 and triggering downstream signaling. EPAC2 signaling can cross-talk with other pathways and is distinguished from PKA-mediated cAMP signals.

In the nervous system, EPAC2 regulates synaptic transmission, dendritic spine morphology and plasticity, and neurotransmitter release, contributing to learning and memory processes. In pancreatic beta cells, EPAC2 contributes to glucose-stimulated insulin secretion via Rap1-mediated exocytosis. Genetic and functional studies have linked RAPGEF4 to certain neuropsychiatric phenotypes, though findings remain context-dependent.

Modulation of EPAC2 activity by selective small molecules has enabled dissection of Epac-dependent pathways; selective activators and inhibitors are used in research to delineate PKA-independent cAMP signaling in metabolism and neuroscience.