| Budget Amount *help |
¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Outline of Final Research Achievements |
The incretin hormones potentiate insulin secretion by PKA-dependent and independent mechanisms, the latter involving Epac2A, which activates small G-protein Rap1. Epac2A is also a target of sulfonylureas (SU)s, widely used drugs in treatment of diabetes. In this study, the mechanism underlying the activation of Epac2A by SU was examined. Molecular docking simulation predicted the amino acid residues of Epac2A that interact with SUs. The predicted amino acids were mutated individually to alanine. Analyses of these mutants by FRET, SU binding, and Rap1 activity revealed that SU-binding site is located in the first cAMP-binding domain A and that binding of SUs to Epac2A depends on SU structures as well as the state of cAMP binding to Epac2A. Also, SU and cAMP synergistically activate Epac2A and its downstream signal Rap1. These data indicate that cAMP and SU cooperatively activate Epac2A through binding to cAMP-binding domain B and cAMP-binding domain A, respectively.
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