Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 325 (5940): 607-610

Copyright © 2009 by the American Association for the Advancement of Science

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

Chang-Liang Zhang,1 Megumi Katoh,1 Tadao Shibasaki,1 Kohtaro Minami,1 Yasuhiro Sunaga,1,* Harumi Takahashi,1 Norihide Yokoi,1 Masahiro Iwasaki,1 Takashi Miki,1 Susumu Seino1,2,3,{dagger}

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.

1 Division 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 Division 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 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency, 4 - 1- 8, Hon-cho,Kawaguchi, Saitoma 332-0012, Japan.

* 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.

{dagger} To whom correspondence should be addressed. E-mail: seino{at}med.kobe-u.ac.jp


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Insulinotropic effect of high potassium concentration beyond plasma membrane depolarization.
M. Belz, M. Willenborg, N. Gorgler, A. Hamada, K. Schumacher, and I. Rustenbeck (2014)
Am J Physiol Endocrinol Metab 306, E697-E706
   Abstract »    Full Text »    PDF »
Meglitinide Analogues in Adolescent Patients With HNF1A-MODY (MODY 3).
M. Becker, A. Galler, and K. Raile (2014)
Pediatrics 133, e775-e779
   Abstract »    Full Text »    PDF »
A Mouse Model of Human Hyperinsulinism Produced by the E1506K Mutation in the Sulphonylurea Receptor SUR1.
K. Shimomura, M. Tusa, M. Iberl, M. F. Brereton, S. Kaizik, P. Proks, C. Lahmann, N. Yaluri, S. Modi, H. Huopio, et al. (2013)
Diabetes 62, 3797-3806
   Abstract »    Full Text »    PDF »
{beta}-Adrenergic Receptors Activate Exchange Protein Directly Activated by cAMP (Epac), Translocate Munc13-1, and Enhance the Rab3A-RIM1{alpha} Interaction to Potentiate Glutamate Release at Cerebrocortical Nerve Terminals.
J. J. Ferrero, A. M. Alvarez, J. Ramirez-Franco, M. C. Godino, D. Bartolome-Martin, C. Aguado, M. Torres, R. Lujan, F. Ciruela, and J. Sanchez-Prieto (2013)
J. Biol. Chem. 288, 31370-31385
   Abstract »    Full Text »    PDF »
Antidiabetic Sulfonylureas and cAMP Cooperatively Activate Epac2A.
T. Takahashi, T. Shibasaki, H. Takahashi, K. Sugawara, A. Ono, N. Inoue, T. Furuya, and S. Seino (2013)
Science Signaling 6, ra94
   Abstract »    Full Text »    PDF »
Local cAMP signaling in disease at a glance.
M. G. Gold, T. Gonen, and J. D. Scott (2013)
J. Cell Sci. 126, 4537-4543
   Abstract »    Full Text »    PDF »
Pancreatic {beta}-Cell Response to Increased Metabolic Demand and to Pharmacologic Secretagogues Requires EPAC2A.
W.-J. Song, P. Mondal, Y. Li, S. E. Lee, and M. A. Hussain (2013)
Diabetes 62, 2796-2807
   Abstract »    Full Text »    PDF »
EPAC Inhibition of SUR1 Receptor Increases Glutamate Release and Seizure Vulnerability.
K. Zhao, R. Wen, X. Wang, L. Pei, Y. Yang, Y. Shang, N. Bazan, L.-Q. Zhu, Q. Tian, and Y. Lu (2013)
J. Neurosci. 33, 8861-8865
   Abstract »    Full Text »    PDF »
Achieving "PeaK-A" Insulin Secretion.
C. Evans-Molina and R. G. Mirmira (2013)
Diabetes 62, 1389-1390
   Full Text »    PDF »
{beta}-Cell-Specific Protein Kinase A Activation Enhances the Efficiency of Glucose Control by Increasing Acute-Phase Insulin Secretion.
K. A. Kaihara, L. M. Dickson, D. A. Jacobson, N. Tamarina, M. W. Roe, L. H. Philipson, and B. Wicksteed (2013)
Diabetes 62, 1527-1536
   Abstract »    Full Text »    PDF »
Tolbutamide Controls Glucagon Release From Mouse Islets Differently Than Glucose: Involvement of KATP Channels From Both {alpha}-Cells and {delta}-Cells.
R. Cheng-Xue, A. Gomez-Ruiz, N. Antoine, L. A. Noel, H.-Y. Chae, M. A. Ravier, F. Chimienti, F. C. Schuit, and P. Gilon (2013)
Diabetes 62, 1612-1622
   Abstract »    Full Text »    PDF »
Exchange Protein Directly Activated by cAMP (epac): A Multidomain cAMP Mediator in the Regulation of Diverse Biological Functions.
M. Schmidt, F. J. Dekker, and H. Maarsingh (2013)
Pharmacol. Rev. 65, 670-709
   Abstract »    Full Text »    PDF »
Enhanced Leptin Sensitivity, Reduced Adiposity, and Improved Glucose Homeostasis in Mice Lacking Exchange Protein Directly Activated by Cyclic AMP Isoform 1.
J. Yan, F. C. Mei, H. Cheng, D. H. Lao, Y. Hu, J. Wei, I. Patrikeev, D. Hao, S. J. Stutz, K. T. Dineley, et al. (2013)
Mol. Cell. Biol. 33, 918-926
   Abstract »    Full Text »    PDF »
Potentiation of Sulfonylurea Action by an EPAC-selective cAMP Analog in INS-1 Cells: Comparison of Tolbutamide and Gliclazide and a Potential Role for EPAC Activation of a 2-APB-sensitive Ca2+ Influx.
R. E. Jarrard, Y. Wang, A. E. Salyer, E. P. S. Pratt, I. M. Soderling, M. L. Guerra, A. M. Lange, H. J. Broderick, and G. H. Hockerman (2013)
Mol. Pharmacol. 83, 191-205
   Abstract »    Full Text »    PDF »
Mechanisms of current therapies for diabetes mellitus type 2.
P. M. Thule (2012)
Advan Physiol Educ 36, 275-283
   Abstract »    Full Text »    PDF »
Isoform-specific antagonists of exchange proteins directly activated by cAMP.
T. Tsalkova, F. C. Mei, S. Li, O. G. Chepurny, C. A. Leech, T. Liu, G. G. Holz, V. L. Woods Jr., and X. Cheng (2012)
PNAS 109, 18613-18618
   Abstract »    Full Text »    PDF »
Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis.
H. Kasai, N. Takahashi, and H. Tokumaru (2012)
Physiol Rev 92, 1915-1964
   Abstract »    Full Text »    PDF »
Ca2+-dependent desensitization of insulin secretion by strong potassium depolarization.
M. Willenborg, M. Belz, K. Schumacher, A. Paufler, K. Hatlapatka, and I. Rustenbeck (2012)
Am J Physiol Endocrinol Metab 303, E223-E233
   Abstract »    Full Text »    PDF »
Rap1 Promotes Multiple Pancreatic Islet Cell Functions and Signals through Mammalian Target of Rapamycin Complex 1 to Enhance Proliferation.
P. Kelly, C. L. Bailey, P. T. Fueger, C. B. Newgard, P. J. Casey, and M. E. Kimple (2010)
J. Biol. Chem. 285, 15777-15785
   Abstract »    Full Text »    PDF »
Differential Phosphorylation of RhoGDI Mediates the Distinct Cycling of Cdc42 and Rac1 to Regulate Second-phase Insulin Secretion.
Z. Wang and D. C. Thurmond (2010)
J. Biol. Chem. 285, 6186-6197
   Abstract »    Full Text »    PDF »
Epac2: A Molecular Target for Sulfonylurea-Induced Insulin Release.
S. A. Hinke (2009)
Science Signaling 2, pe54
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882