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The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs

Science, 31 July 2009
Vol. 325, Issue 5940, p. 607-610
DOI: 10.1126/science.1172256

The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs

  1. Chang-Liang Zhang1,
  2. Megumi Katoh1,
  3. Tadao Shibasaki1,
  4. Kohtaro Minami1,
  5. Yasuhiro Sunaga1,*,
  6. Harumi Takahashi1,
  7. Norihide Yokoi1,
  8. Masahiro Iwasaki1,
  9. Takashi Miki1,
  10. Susumu Seino1,2,3,
  1. 1Division of Cellular and Molecular Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
  2. 2Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
  3. 3Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 4 - 1- 8, Hon-cho,Kawaguchi, Saitoma 332-0012, Japan.
  1. To whom correspondence should be addressed. E-mail: seino{at}med.kobe-u.ac.jp

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.

  • * Present address: Cell Scale Team, Integrated Simulation of Living Matter Group, Computational Science Research Program, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.

  • Received for publication 13 February 2009.
  • Accepted for publication 19 June 2009.

Citation:

C.-L. Zhang, M. Katoh, T. Shibasaki, K. Minami, Y. Sunaga, H. Takahashi, N. Yokoi, M. Iwasaki, T. Miki, and S. Seino, The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs. Science 325, 607-610 (2009).

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