在禁食狀態(tài),，體液中循環(huán)的胰高血糖素的增加通過誘導(dǎo)糖原異生作用，促進(jìn)了肝臟葡萄糖的產(chǎn)生,。促發(fā)cAMP信號通路,，通過CREB輔激活因子CRTC2的去磷酸化，提升了糖原異生基因的表達(dá),。胰高血糖素在一定程度上通過蛋白激酶A（PKA)介導(dǎo)的對CRTC2激酶SIK2的抑制作用,，促進(jìn)了CRTC2的去磷酸化。
已知許多Ser/Thr磷酸酶似乎都能引起CRTC2的去磷酸化,，但是通過哪種激素信號來調(diào)節(jié)這些酶還不可知,。
近日,，美國哥倫比亞大學(xué)的研究人員發(fā)現(xiàn)，老鼠的胰高血糖素通過動員細(xì)胞內(nèi)的鈣存儲,，激活鈣/鈣調(diào)蛋白依賴的Ser/Thr磷酸化酶（又稱為PP3CA）,，促進(jìn)了肝細(xì)胞中CRTC2的去磷酸化。胰高血糖素通過PKA介導(dǎo)的肌醇三磷酸受體(InsP3Rs)的磷酸化,，提升了細(xì)胞質(zhì)基質(zhì)的鈣濃度,。激活的InsP3Rs促進(jìn)了磷酸酶介導(dǎo)的CRCT2的去磷酸化作用，增強(qiáng)了糖原異生基因的表達(dá),。
在進(jìn)食期間,，胰島素的表達(dá)增加，通過AKT介導(dǎo)的InsP3Rs的失活,，降低了CRCT2的活性,。而在糖尿病患者中，InsP3R的活性被提高,，導(dǎo)致了糖原異生作用的上調(diào),。
在胰島素抗性背景下，肝內(nèi)InsP3Rs以及磷酸酶的下調(diào)提升了循環(huán)的葡萄糖的水平,。這些結(jié)果闡明了在禁食及糖尿病InsP3Rs調(diào)節(jié)肝臟葡萄糖的機(jī)制,。相關(guān)論文于4月8日在Nature上在線發(fā)表。（生物谷Deepblue編譯）
doi: 10.1038/nature10988
PMC:
PMID:
Inositol-1,4,5-trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes
Yiguo Wang,Gang Li,Jason Goode, Jose C. Paz, Kunfu Ouyang, Robert Screaton, Wolfgang H. Fischer, Ju Chen, Ira Tabas & Marc Montminy.
In the fasted state, increases in circulating glucagon promote hepatic glucose production through induction of the gluconeogenic program.Triggering of the cyclic AMP pathway increases gluconeogenic gene expression via the de-phosphorylation of the CREB co-activator CRTC2.Glucagon promotes CRTC2 dephosphorylation in part through the protein kinase A (PKA)-mediated inhibition of the CRTC2 kinase SIK2. A number of Ser/Thr phosphatases seem to be capable of dephosphorylating CRTC2, but the mechanisms by which hormonal cues regulate these enzymes remain unclear.Here we show in mice that glucagon stimulates CRTC2 dephosphorylation in hepatocytes by mobilizing intracellular calcium stores and activating the calcium/calmodulin-dependent Ser/Thr-phosphatase calcineurin (also known as PP3CA).Glucagon increased cytosolic calcium concentration through the PKA-mediated phosphorylation of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which associate with CRTC2. After their activation, InsP3Rs enhanced gluconeogenic gene expression by promoting the calcineurin-mediated dephosphorylation of CRTC2.During feeding, increases in insulin signalling 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 downregulation of InsP3Rs and calcineurin improved circulating glucose levels in insulin resistance, these results demonstrate how interactions between cAMP and calcium pathways at the level of the InsP3R modulate hepatic glucose production under fasting conditions and in diabetes.
