The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs
The cAMP Sensor Epac2 Is a Direct Target of Antidiabetic Sulfonylurea Drugs
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DOI：
10.1126/science.1172256
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发表时间：
2009-07-31
期刊：
影响因子：
56.9
通讯作者：
Seino, Susumu
中科院分区：
文献类型：
--
作者：
Zhang, Chang-Liang;Katoh, Megumi;Seino, Susumu
Epac2 是小鸟苷三磷酸酶 Rap1 的鸟嘌呤核苷酸交换因子，由 3',5'-单磷酸腺苷激活。荧光共振能量转移和结合实验表明，广泛使用的抗糖尿病药物磺酰脲类药物可直接与 Epac2 相互作用。磺酰脲类药物通过 Epac2 特异性激活 Rap1。在缺乏Epac2的小鼠中，磺酰脲类刺激的胰岛素分泌在体外和体内均减少，并且磺酰脲类甲苯磺丁脲的降血糖作用在这些小鼠中也降低。因此，Epac2有助于磺酰脲类药物促进胰岛素分泌的作用。由于 Epac2 也是肠促胰岛素（对于增强胰岛素分泌至关重要的肠道激素）的作用所必需的，因此它可能是抗糖尿病药物开发的一个有前景的靶标。
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.