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It has been reported by Zhang et al. that antidiabetic sulfonylurea drugs promote insulin secretion by directly binding to exchange protein directly activated by cyclic AMP isoform 2 (Epac2) and activating its down-stream effector Rap1. However, a critical link for an unambiguous validation of a direct interaction between Epac2 and sulfonylurea using purified individual components is missing. Our in vitro analyses using purified full-length Epac2 and Rap1 suggest that sulfonylureas are not able to directly bind to Epac2, nor are they capable of triggering Epac2-dependent Rap1 activation.

Exchange Protein Directly Activated by Cyclic AMP Isoform 2 Is Not a Direct Target of Sulfonylurea Drugs