"EPAC1: Molecular architecture, physiological regulation, and therapeutic implications in diseases"

Exchange Protein Directly Activated by cAMP 1 (EPAC1) is an intracellular effector of the small GTPases Rap1 and Rap2, functioning independently of protein kinase A in the cAMP signalling pathway. The structural analysis shows that EPAC1 has an N-terminal regulatory region comprising a Dishevelled, Egl-10, and Pleckstrin (DEP) domain and a cyclic nucleotide-binding domain (cNBD) with a phosphate binding cassette (PBC) for cAMP binding, and a C-terminal catalytic region comprising Ras exchange motif, Ras association and a CDC25 homology domain (CDC25-HD). Although EPAC1 is broadly expressed, it has tissue-specific functions in endothelial barrier regulation, cardiac calcium homeostasis, vascular tone, metabolism, insulin secretion, and nociception. Dysregulation leads to cardiovascular hypertrophy, failure, diabetes-associated complications, inflammation, neuropathic pain, and cancer. Pharmacological modulation of EPAC1 with agents such as inhibitors CE3F4, AM-001, ESI-09, as well as agonist SY009, SY007 and partial agonist PWO577 holds significant therapeutic potential depending on disease context. The therapeutic effect is based on both EPAC1 activation that improves endothelial activities and glucose-stimulated insulin release, and inhibition that reduces cardiac hypertrophy and chronic pain. For example, SY009 enhances glucose-stimulated insulin secretion, and PWO577 is a Rap1 agonist that suppresses proinflammatory genes during vascular inflammatory conditions. EPAC1 is a versatile pharmaceutical target with transformative therapeutic potential in a broad range of disease pathologies.