RAPGEF4 (Rap guanine nucleotide exchange factor 4), also known as Epac2, is a cAMP-activated guanine nucleotide exchange factor that activates small GTPases RAP1A, RAP1B, and RAP2A 1. The protein functions as a direct cAMP sensor involved in cAMP-mediated signal transduction 1, with primary expression in brain, neuroendocrine, and endocrine tissues 1. Mechanistically, RAPGEF4 regulates diverse cellular processes through calcium-dependent signaling. In pancreatic β-cells, RAPGEF4 mediates GLP-1 receptor agonist-induced autophagy through a calcium-calcineurin-TFEB axis, independent of AMPK/mTOR pathways 2. In neuronal development, RAPGEF4 is critical for maturation of resting membrane potential and inward sodium current in prefrontal cortex neurons, with deficiency in autism-associated CHD8 gene leading to RAPGEF4 downregulation and impaired electrophysiological maturation 3. Disease relevance spans multiple conditions: RAPGEF4 dysregulation associates with type 2 diabetes pathogenesis 2, neuropsychiatric disorders including autism and major depressive disorder 34, polycystic ovary syndrome 5, and sex-specific cardiac fibrosis in aging 6. The rs3769219 polymorphism shows protective effects against depression in males and recurrent depression overall 4. RAPGEF4 represents a potential therapeutic target for metabolic and neuropsychiatric disorders 7.