Direct Activation of Epac by Sulfonylurea Is Isoform Selective

SummaryCommonly 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (238 K)Download as PowerPoint slideHighlights► Sulfonylureas (SUs) activate Epac2 via direct binding to Epac2 ► SU-induced activation of Epac2 leads to Rap1 activation and ERK1/2 phosphorylation ► R447 in Epac2 is critical for SU binding to and activation of Epac2 ► SUs selectively activate Epac2 isoform