Elucidation of the function and role of cAMP sensor Epac2A in insulin secretion

Insulin secretion is regulated by various intracellular signals including Ca²⁺, ATP, cAMP, and phospholipid-derived signals. Although glucose-induced insulin secretion (GIIS) is the principal mechanism of insulin secretion, its potentiation by cAMP is also critical. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-IV inhibitors, both of which are new anti-diabetic drugs, act through cAMP signaling in pancreatic β-cells. cAMP is now known to potentiate insulin secretion by both protein kinase A (PKA)-dependent and PKA-independent mechanisms, the latter involving Epac2A, a protein possessing guanine nucleotide exchange factor activity towards the small G-protein Rap. Total internal reflection fluorescence microscopy analysis revealed that Epac2A/Rap1 signaling is required for potentiation of the first phase of GIIS by cAMP. Epac2A also interacts directly and indirectly with the exocytotic machinery and likely forms a cAMP compartment in a specialized region of the pancreatic β-cell. In addition, Epac2A is activated by sulfonylureas (SUs), widely used anti-diabetic drugs. SU-stimulated insulin secretion is reduced both in vitro and in vivo in mice lacking Epac2A. SUs are known to stimulate insulin secretion by closing pancreatic β-cell ATP-sensitive K⁺ (K_ATP) channels through binding to the SU receptor SUR1, a regulatory subunit of the channel. These findings demonstrate that Epac2A is a direct target of SUs and that it is required in order for SUs to exert their full effects in insulin secretion. Thus, clarification of the molecular mechanisms underlying Epac2A-mediated insulin secretion can provide a basis for understanding the action of the incretins and SU drugs and further development of anti-diabetic drugs.