TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion
TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion
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DOI：
10.1038/sj.emboj.7601083
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发表时间：
2006-05-03
期刊：
影响因子：
11.4
通讯作者：
Tominaga, Makoto
中科院分区：
文献类型：
--
作者：
Togashi, Kazuya;Hara, Yuji;Tominaga, Makoto
哺乳动物体内存在8个温度敏感的TRP通道，可能存在其它对温度敏感的TRP通道。在这里，我们证明了TRPM 2可以通过暴露于温暖的温度（> 35摄氏度）被激活，显然是通过直接热诱发通道门控。β-NAD（+）-或ADP-核糖-诱发的TRPM 2活性在升高的温度下强烈增强。我们还表明，即使环腺苷三磷酸（cADPR）不激活TRPM 2在25摄氏度，共同应用的热量和细胞内cADPR显着增强TRPM 2的活性。热和cADPR在内源性表达TRPM 2的大鼠胰岛素瘤RIN-5 F细胞中引起类似的反应。在胰岛中，TRPM 2与胰岛素共表达，并且这些细胞的温和加热引起胞质Ca 2+和胰岛素释放的增加，这是K-ATP通道非依赖性和蛋白激酶A介导的。在RIN-5 F细胞和胰岛中的热诱发反应通过用TRPM 2特异性siRNA处理而显著减弱。这些结果将TRPM 2鉴定为cADPR的潜在分子靶点，并表明TRPM 2在体温下依赖于cADPR相关分子的产生调节Ca 2+进入胰腺B-细胞，从而调节胰岛素分泌。
There are eight thermosensitive TRP (transient receptor potential) channels in mammals, and there might be other TRP channels sensitive to temperature stimuli. Here, we demonstrate that TRPM2 can be activated by exposure to warm temperatures (> 35 degrees C) apparently via direct heat-evoked channel gating. beta-NAD(+)- or ADP-ribose-evoked TRPM2 activity is robustly potentiated at elevated temperatures. We also show that, even though cyclic ADPribose (cADPR) does not activate TRPM2 at 25 degrees C, co-application of heat and intracellular cADPR dramatically potentiates TRPM2 activity. Heat and cADPR evoke similar responses in rat insulinoma RIN-5F cells, which express TRPM2 endogenously. In pancreatic islets, TRPM2 is co-expressed with insulin, and mild heating of these cells evokes increases in both cytosolic Ca2+ and insulin release, which is K-ATP channel-independent and protein kinase A-mediated. Heat-evoked responses in both RIN-5F cells and pancreatic islets are significantly diminished by treatment with TRPM2-specific siRNA. These results identify TRPM2 as a potential molecular target for cADPR, and suggest that TRPM2 regulates Ca2+ entry into pancreatic b- cells at body temperature depending on the production of cADPR-related molecules, thereby regulating insulin secretion.