厦门大学林圣彩课题组揭示了瞬时受体电位通道亚家族V (TRPV)通道是醛糖酶和AMP激活的蛋白激酶(AMPK)葡萄糖传感的关键通道。该项研究成果于2019年9月3日发表在《细胞—代谢》杂志上。

他们表示未被果糖-1,6-二磷酸（FBP）占据的醛缩酶与内质网（ER）定位的瞬时TRPV相互作用并抑制其功能，以抑制低葡萄糖中的钙释放。 ER和溶酶体之间接触部位的钙的减少使得被抑制的TRPV可以与溶酶体v-ATP酶结合，然后募集AXIN：LKB1以激活不依赖于AMP的AMPK。 TRPV的遗传学敲除阻断小鼠细胞中的和肝脏的葡萄糖饥饿诱导的AMPK的激活，以及在线虫中也表征TRPV是基本物理需求。TRPV的药理学抑制激活AMPK并提高老年肌肉中的NAD +水平，使动物的运行能力恢复活力。他们的研究阐明TRPVs将没有FBP占据的醛缩酶传递给v-ATPase，进行构象重构，导致低葡萄糖中的AMPK活化。

据悉， FBP醛缩酶通过溶酶体途径将葡萄糖可用性下降信号与AMPK活化信号联系起来。然而，醛缩酶如何传递未被FBP占据的信号来激活AMPK的仍不清楚。

附：英文原文

Title: Transient Receptor Potential V Channels Are Essential for Glucose Sensing by Aldolase and AMPK

Author: Mengqi Li 8,Chen-Song Zhang 8,Yue Zong 8,Jin-Wei Feng,Teng Ma,Meiqin Hu,Zhizhong Lin,Xiaotong Li,Changchuan Xie,Yaying Wu,Dong Jiang,Ying Li,Cixiong Zhang,Xiao Tian,Wen Wang,Yanyan Yang,Jie Chen,Jiwen Cui,Yu-Qing Wu,Xin Chen,Qing-Feng Liu,Jianfeng Wu,Shu-Yong Lin,Zhiyun Ye,Ying Liu,Hai-Long Piao,Li Yu,Zhuan Zhou,Xiao-Song Xie,D. Grahame Hardie,Sheng-Cai Lin

Issue&Volume: Volume 30 Issue 3

Abstract: Fructose-1,6-bisphosphate (FBP) aldolase links sensing of declining glucose availability to AMPK activation via the lysosomal pathway. However, how aldolase transmits lack of occupancy by FBP to AMPK activation remains unclear. Here, we show that FBP-unoccupied aldolase interacts with and inhibits endoplasmic reticulum (ER)-localized transient receptor potential channel subfamily V, inhibiting calcium release in low glucose. The decrease of calcium at contact sites between ER and lysosome renders the inhibited TRPV accessible to bind the lysosomal v-ATPase that then recruits AXIN:LKB1 to activate AMPK independently of AMP. Genetic depletion of TRPVs blocks glucose starvation-induced AMPK activation in cells and liver of mice, and in nematodes, indicative of physical requirement of TRPVs. Pharmacological inhibition of TRPVs activates AMPK and elevates NAD+ levels in aged muscles, rejuvenating the animals’ running capacity. Our study elucidates that TRPVs relay the FBP-free status of aldolase to the reconfiguration of v-ATPase, leading to AMPK activation in low glucose.

DOI: https://doi.org/10.1016/j.cmet.2019.05.018

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30258-X