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  • br Declaration of conflicting interests br Funding The


    Declaration of conflicting interests
    Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by CT Stem Cell grant # 15-RMB-YALE-07 (to L.E.N), and by an unrestricted Research Gift from Humacyte, Inc. (to L.E.N).
    Cyclic adenosine monophosphate (cAMP), also known as 3′,5′-cyclic adenosine monophosphate, is converted from sennoside by adenylate cyclases (ACs). It is a prototypic second messenger that plays crucial roles in cellular responses to various stimulations, and mediates signaling pathways related to many human diseases including cancer, cardiac and urinary dysfunction, diabetes, immunological diseases and nerve disease., , , Protein kinase A (PKA) and cyclic nucleotide-regulated ion channels were the first discovered cAMP mediators and originally considered as the only ones. In 1998, two independent groups reported another cAMP mediator named exchange proteins directly activated by cAMP (EPACs)., EPAC is a family of cAMP-binding proteins with guanine nucleotide exchange factors (GEF) activity that directly activate Ras-like small GTPases (Rap1 and Rap2)., The discovery of EPAC proteins has significantly facilitated the understanding of cAMP-dependent signaling pathway and opens new avenues for developing novel therapeutics targeting cancer, diabetes, heart failure, inflammation, infectious diseases, neurological disorders and other human conditions., , , , To date, two members of the EPAC family proteins have been identified, known as EPAC1 (coded by gene, in human) and EPAC2 (coded by gene, in human)., EPAC1 (cAMP-GEF-I) is an about 100kDa molecular weight multi-domain protein that is highly expressed in developing and mature human tissues. The multi-domain protein EPAC2 has three isoforms (EPAC2A, EPAC2B and EPAC2C) with about 115kDa of molecular weight and is enriched in nervous system and endocrine tissues. EPAC1 and EPAC2 proteins have considerable similarity in the structure and sequence (68% similarity in human). Both EPAC1 and EPAC2 consist of two regions, the N-terminal regulatory region and the C-terminal catalytic region. The regulatory region of EPAC protein includes a disheveled, Egl-10, pleckstrin (DEP) domain and cyclic nucleotide binding domain (CNBD). The C-terminal catalytic regions of EPAC1 and EPAC2 are composed of three basic domains named as cell division cycle 25 homology GEF domain (CDC25-HD), Ras association (RA) domain, and Ras exchange motif (REM) domain., In the absence of cAMP, the activity of EPAC is auto-inhibited. The N-terminal regulatory region and the C-terminal catalytic region of EPAC are held together through intramolecular interactions, thereby preventing Rap binding to the CDC25-HD of EPAC and keeping EPAC inactive (). When cell is stimulated by extracellular signals, ACs are activated through various ligands which bind to G-protein-coupled receptors (GPCRs) and promote the conversion of ATP into cAMP. The binding of cAMP to CNBD allows the regulatory region to rotate about 90° sideways and leaves enough space for Rap binding to CDC25-HD. Consequently, active EPAC catalyzes the exchange of guanosine diphosphate (GDP) to guanosine triphosphate (GTP) and controls Rap-mediated biological functions (). The EPAC signaling pathway plays a critical role in various biological responses including insulin secretion, neuronal function, cardiovascular function, vascular function, inflammation, cancer, pain, and infections., , , , The EPAC signaling pathway is involved in insulin secretion from pancreatic β cells. EPAC2 promotes glucose-stimulated insulin secretion (GSIS) by regulation of intracellular Ca concentration., , To date, three pathways have been revealed for EPAC2-mediated insulin secretion. First, EPAC2/Rap can activate phospholipase Cε (PLCε), protein kinase C (PKC), ryanodine receptor (RyR) and sarco/endoplasmic reticulum Ca-ATPase (SERCA)., Second, EPAC2 can directly interact with sulfonylurea receptor 1 (SUR1), leading to ATP-sensitive potassium channel (K) closure in response to the increase in the ATP/ADP ratio, thus regulating the intracellular Ca level. Third, interaction of EPAC2 with Rim2, Munc 13-1 and Piccolo potentiates rapid Ca-dependent exocytosis., According to a recent study, EPAC1 may also play an important role in GSIS. The EPAC1 knockout mouse model showed the decreased expression of glucose transporter Glut2 and transcription factor PDX1. Collectively, these studies suggest that EPAC represents a potential therapeutic target for diabetes and obesity.