Glucose-Sensing Receptor T1R3: A New Signaling Receptor Activated by Glucose in Pancreatic β-Cells
Glucose-Sensing Receptor T1R3: A New Signaling Receptor Activated by Glucose in Pancreatic β-Cells
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DOI：
10.1248/bpb.b14-00895
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发表时间：
2015-05-01
影响因子：
2
通讯作者：
Nagasawa, Masahiro
中科院分区：
文献类型：
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作者：
Kojima, Itaru;Nakagawa, Yuko;Nagasawa, Masahiro
甜味受体T1 R2和T1 R3的亚基在胰腺β细胞中表达。与T1 R3相比，T1 R2的mRNA表达显著降低。在蛋白质水平，T1 R2的表达在β细胞中是不可检测的。因此，β-细胞中甜味感测受体的主要组分可能是T1 R3的同源二聚体，而不是T1 R2/T1 R3的异源二聚体。通过gurmarin或T1 R3基因缺失抑制该受体可减弱葡萄糖诱导的β细胞胰岛素分泌。因此，T1 R3同二聚体在胰腺β细胞中充当葡萄糖敏感受体（GSR）。当GSR被T1 R3激动剂三氯蔗糖激活时，观察到细胞内ATP浓度（[ATP]（i））升高。即使在没有环境葡萄糖的情况下，三氯蔗糖也会增加[ATP]（i），这表明三氯蔗糖增加[ATP]（i）不仅仅是通过激活葡萄糖激酶（糖酵解途径中的限速酶）。此外，三氯蔗糖增强琥珀酸甲酯诱导的[ATP]（i）升高，表明三氯蔗糖激活线粒体代谢。非代谢性3-O-甲基葡萄糖也会增加[ATP]（i），T1 R3的敲低会减弱高浓度葡萄糖诱导的[ATP]（i）升高。总的来说，这些结果表明T1 R3同二聚体作为GSR发挥功能;该受体通过激活线粒体中的葡萄糖代谢参与葡萄糖诱导的胰岛素分泌。
Subunits of the sweet taste receptors T1R2 and T1R3 are expressed in pancreatic beta-cells. Compared with T1R3, mRNA expression of T1R2 is considerably lower. At the protein level, expression of T1R2 is un-detectable in beta-cells. Accordingly, a major component of the sweet taste-sensing receptor in beta-cells may be a homodimer of T1R3 rather than a heterodimer of T1R2/T1R3. Inhibition of this receptor by gurmarin or deletion of the T1R3 gene attenuates glucose-induced insulin secretion from beta-cells. Hence the T1R3 homodimer functions as a glucose-sensing receptor (GSR) in pancreatic beta-cells. When GSR is activated by the T1R3 agonist sucralose, elevation of intracellular ATP concentration ([ATP](i)) is observed. Sucralose increases [ATP](i) even in the absence of ambient glucose, indicating that sucralose increases [ATP](i) not simply by activating glucokinase, a rate-limiting enzyme in the glycolytic pathway. In addition, sucralose augments elevation of [ATP](i) induced by methylsuccinate, suggesting that sucralose activates mitochondrial metabolism. Nonmetabolizable 3-O-methylglucose also increases [ATP](i) and knockdown of T1R3 attenuates elevation of [ATP](i) induced by high concentration of glucose. Collectively, these results indicate that the T1R3 homodimer functions as a GSR; this receptor is involved in glucose-induced insulin secretion by activating glucose metabolism probably in mitochondria.