title: Direct activation of Epac by sulfonylurea is isoform selective.
abstract: Commonly used as a treatment for Type II diabetes, sulfonylureas (SUs) stimulate insulin secretion from pancreatic β cells by binding to sulfonylurea receptors. Recently, SUs have been shown to also activate exchange protein directly activated by cAMP 2 (Epac2), however, little is known about this molecular action. Using biosensor imaging and biochemical analysis, we show that SUs activate Epac2 and the downstream signaling via direct binding to Epac2. We further identify R447 of Epac2 to be critically involved in SU binding. This distinct binding site from cAMP points to a new mode of allosteric activation of Epac2. We also show that SUs selectively activate Epac2 isoform, but not the closely related Epac1, further establishing SUs as a new class of isoform-selective enzyme activators.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Herbst
authors.forename: Carla
authors.initials: C
authors.lastname: Coltharp
authors.forename: L Mario
authors.initials: LM
authors.lastname: Amzel
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D001120:Arginine; D001665:Binding Sites; D015374:Biosensing Techniques; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D031541:Fluorescence Resonance Energy Transfer; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008958:Models, Molecular; D009068:Movement; D011487:Protein Conformation / Q000187:drug effects; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013379:Substrate Specificity; D013453:Sulfonylurea Compounds / Q000378:metabolism / Q000494:pharmacology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D020033:Protein Isoforms; D013453:Sulfonylurea Compounds; D001120:Arginine; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020827:rap1 GTP-Binding Proteins