Direct activation of Epac by sulfonylurea is isoform selective

Katie J. Herbst, Carla Coltharp, L. Mario Amzel, Jin Zhang

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)243-251
Number of pages9
JournalChemistry and Biology
Volume18
Issue number2
DOIs
StatePublished - Feb 25 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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