RRC ID 72046
Author Zhang CL, Katoh M, Shibasaki T, Minami K, Sunaga Y, Takahashi H, Yokoi N, Iwasaki M, Miki T, Seino S.
Title The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs.
Journal Science
Abstract Epac2, a guanine nucleotide exchange factor for the small guanosine triphosphatase Rap1, is activated by adenosine 3',5'-monophosphate. Fluorescence resonance energy transfer and binding experiments revealed that sulfonylureas, widely used antidiabetic drugs, interact directly with Epac2. Sulfonylureas activated Rap1 specifically through Epac2. Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, and the glucose-lowering effect of the sulfonylurea tolbutamide was decreased in these mice. Epac2 thus contributes to the effect of sulfonylureas to promote insulin secretion. Because Epac2 is also required for the action of incretins, gut hormones crucial for potentiating insulin secretion, it may be a promising target for antidiabetic drug development.
Volume 325(5940)
Pages 607-10
Published 2009-7-31
DOI 10.1126/science.1172256
PII 325/5940/607
PMID 19644119
MeSH 8-Bromo Cyclic Adenosine Monophosphate / pharmacology Animals Blood Glucose / analysis COS Cells Carrier Proteins / genetics Carrier Proteins / metabolism* Cell Line Chlorocebus aethiops Cyclic AMP / metabolism* Fluorescence Resonance Energy Transfer Glucose / administration & dosage Glyburide / metabolism Glyburide / pharmacology Guanine Nucleotide Exchange Factors / genetics Guanine Nucleotide Exchange Factors / metabolism* Hypoglycemic Agents / chemistry Hypoglycemic Agents / metabolism* Hypoglycemic Agents / pharmacology Insulin / blood Insulin / metabolism Insulin Secretion Islets of Langerhans / metabolism Mice Mice, Inbred C57BL Sulfonylurea Compounds / chemistry Sulfonylurea Compounds / metabolism* Sulfonylurea Compounds / pharmacology Tolbutamide / metabolism Tolbutamide / pharmacology rap1 GTP-Binding Proteins / metabolism
IF 41.846
DNA material C-Epac2-Y (RDB19602)