Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.
Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes.
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DOI：
10.1038/nature10988
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发表时间：
2012-04-08
期刊：
影响因子：
64.8
通讯作者：
Montminy, Marc
中科院分区：
文献类型：
--
作者：
Wang, Yiguo;Li, Gang;Goode, Jason;Paz, Jose C.;Ouyang, Kunfu;Screaton, Robert;Fischer, Wolfgang H.;Chen, Ju;Tabas, Ira;Montminy, Marc
在禁食状态下，循环中的高血糖素通过诱导糖异生程序促进肝脏葡萄糖的产生。CAMP途径的触发通过CREB辅活化子CRTC2的去磷酸化增加了糖异生基因的表达。胰升糖素促进CRTC2去磷酸化的部分途径是通过PKA介导的对CRTC2激酶SIK2的抑制。一些丝氨酸/苏氨酸磷酸酶似乎能够使CRTC2去磷酸化，但激素信号调节这些酶的机制尚不清楚。在这里，我们表明，高血糖素通过动员细胞内钙储存和激活钙/钙调蛋白依赖的丝氨酸/苏氨酸磷酸酶钙调神经磷酸酶/PP2B来刺激肝细胞CRTC2去磷酸化。胰升糖素通过PKA介导的肌醇1，4，5-三磷酸受体(InsP3Rs)的磷酸化来增加细胞内钙，我们在这里发现这与CRTC2有关。在激活后，InsP3Rs通过促进钙调神经磷酸酶介导的CRTC2的去磷酸化来增强糖异生基因的表达。在喂养过程中，胰岛素信号的增加通过AKT介导的InsP3Rs失活降低了CRTC2的活性。在糖尿病患者中，InsP3R活性增加，导致糖异生程序上调。随着InsP3Rs和钙调神经磷酸酶在胰岛素抵抗中的肝脏下调改善循环血糖水平，这些结果证明了在空腹条件下和糖尿病中，cAMP和钙通路之间在InsP3受体水平上的串扰是如何调节肝脏葡萄糖产生的。
In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program. Triggering of the cAMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB coactivator CRTC2 . Glucagon promotes CRTC2 dephosphorylation in part through the PKA-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases appear capable of dephosphorylating CRTC2 , but the mechanisms by which hormonal cues regulate these enzymes remain unclear. Here we show that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin dependent Ser/Thr phosphatase calcineurin/PP2B. Glucagon increased cytosolic calcium through the PKA-mediated phosphorylation of inositol 1,4,5-trisphosphate receptors (InsP3Rs), which we show here associate with CRTC2. Following their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2. During feeding, increases in insulin signaling reduced CRTC2 activity via the AKT-mediated inactivation of InsP3Rs. InsP3R activity was increased in diabetes, leading to upregulation of the gluconeogenic program. As hepatic down-regulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how cross-talk between cAMP and calcium pathways at the level of the InsP3 receptor modulates hepatic glucose production under fasting conditions and in diabetes.
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影响因子：
64.8
作者：
Liu, Yi;Dentin, Renaud;Chen, Danica;Hedrick, Susan;Ravnskjaer, Kim;Schenk, Simon;Milne, Jill;Meyers, David J.;Cole, Phil;Yates, John, III;Olefsky, Jerrold;Guarente, Leonard;Montminy, Marc
通讯作者：
Montminy, Marc
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
13.5
作者：
Cruz, Laura N.;Guerra, Mateus T.;Kruglov, Emma;Mennone, Albert;Garcia, Celia R. S.;Chen, Ju;Nathanson, Michael H.
通讯作者：
Nathanson, Michael H.
影响因子：
64.8
作者：
WAKELAM, MJO;MURPHY, GJ;HOUSLAY, MD
通讯作者：
HOUSLAY, MD
DOI：
10.1073/pnas.1012665107
发表时间：
2010-10-12
影响因子：
11.1
作者：
Yoon, Young-Sil;Lee, Min-Woo;Koo, Seung-Hoi
通讯作者：
Koo, Seung-Hoi