Glucose Evokes Rapid Ca2+ and Cyclic AMP Signals by Activating the Cell-Surface Glucose-Sensing Receptor in Pancreatic β-Cells
Glucose Evokes Rapid Ca2+ and Cyclic AMP Signals by Activating the Cell-Surface Glucose-Sensing Receptor in Pancreatic β-Cells
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DOI：
10.1371/journal.pone.0144053
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发表时间：
2015-12-02
期刊：
影响因子：
3.7
通讯作者：
Kojima, Itaru
中科院分区：
文献类型：
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作者：
Nakagawa, Yuko;Nagasawa, Masahiro;Kojima, Itaru
葡萄糖是胰腺β细胞中胰岛素分泌的主要刺激剂。人们认为高浓度的葡萄糖仅通过其新陈代谢发挥其作用。在这方面，我们最近报道葡萄糖还可以激活细胞表面的葡萄糖敏感受体并促进其自身的代谢。在本研究中，我们研究了葡萄糖是否激活葡萄糖感应受体并引发受体介导的快速作用。在 MIN6 细胞和分离的小鼠 β 细胞中，葡萄糖诱导细胞质 Ca2+ 浓度的三相变化 ([Ca2+](c))；葡萄糖引起 [Ca2+](c) 立即升高，随后 [Ca2+](c) 降低，经过一定的滞后期后，它引起 [Ca2+](c) 大幅振荡升高。 [Ca2+](c) 的初始快速峰值和随后的减少与葡萄糖代谢无关，并由不可代谢的葡萄糖类似物再现。这些信号也被 T1R3（葡萄糖敏感受体的一个亚基）抑制剂和 T1R3 基因的缺失所阻断。除了 Ca2+ 之外，葡萄糖还诱导细胞内 cAMP ([cAMP](c)) 立即和持续升高。 [cAMP](c) 的升高被显性失活 G(s) 的转导和 T1R3 基因的删除所阻断。这些结果表明，葡萄糖通过激活细胞表面葡萄糖敏感受体，诱导 [Ca2+](c) 和 [cAMP](c) 快速变化。因此，葡萄糖通过激活细胞表面受体产生快速的细胞内信号。
Glucose is a primary stimulator of insulin secretion in pancreatic beta-cells. High concentration of glucose has been thought to exert its action solely through its metabolism. In this regard, we have recently reported that glucose also activates a cell-surface glucose-sensing receptor and facilitates its own metabolism. In the present study, we investigated whether glucose activates the glucose-sensing receptor and elicits receptor-mediated rapid actions. In MIN6 cells and isolated mouse beta-cells, glucose induced triphasic changes in cytoplasmic Ca2+ concentration ([Ca2+](c)); glucose evoked an immediate elevation of [Ca2+](c), which was followed by a decrease in [Ca2+](c), and after a certain lag period it induced large oscillatory elevations of [Ca2+](c). Initial rapid peak and subsequent reduction of [Ca2+](c) were independent of glucose metabolism and reproduced by a nonmetabolizable glucose analogue. These signals were also blocked by an inhibitor of T1R3, a subunit of the glucose-sensing receptor, and by deletion of the T1R3 gene. Besides Ca2+, glucose also induced an immediate and sustained elevation of intracellular cAMP ([cAMP](c)). The elevation of [cAMP](c) was blocked by transduction of the dominant-negative G(s), and deletion of the T1R3 gene. These results indicate that glucose induces rapid changes in [Ca2+](c) and [cAMP](c) by activating the cell-surface glucose-sensing receptor. Hence, glucose generates rapid intracellular signals by activating the cell-surface receptor.