Research ArticlePharmacology

Antidiabetic Sulfonylureas and cAMP Cooperatively Activate Epac2A

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Science Signaling  22 Oct 2013:
Vol. 6, Issue 298, pp. ra94
DOI: 10.1126/scisignal.2004581

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Cooperation Between cAMP and Antidiabetic Drugs

A class of drugs called sulfonylureas increase insulin secretion from pancreatic β cells in patients with type 2 diabetes. One sulfonylurea mechanism for enhancing insulin secretion is through stimulation of the guanine nucleotide exchange factor Epac2A. Takahashi et al. used molecular docking simulation to predict the sulfonylurea binding site on Epac2A and verified in cells with site-directed mutants that sulfonylureas bound to one of two cyclic nucleotide–binding domains and cooperated with the endogenous Epac activator cyclic adenosine monophosphate to promote Epac2A function and stimulate the Epac target Rap1. The identification of specific amino acids in Epac2A that mediate interactions with sulfonylureas could help to develop drugs for treating diabetes.