TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species.
TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species.
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DOI：
10.3390/antiox10081243
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发表时间：
2021-08-03
期刊：
影响因子：
--
通讯作者：
Barritt GJ
中科院分区：
文献类型：
--
作者：
Ali ES;Rychkov GY;Barritt GJ
TRPM 2通道允许Ca 2+和Na+穿过质膜并从溶酶体释放Ca 2+和Zn 2+。通道激活由活性氧（ROS）引发，导致随后ADP-核糖增加以及ADP-核糖与胞质NUDT 9同源结构域中的变构位点结合。在许多动物细胞类型中，Ca 2+通过TRPM 2通道进入介导ROS引发的细胞损伤和死亡。本文综述了TRPM 2和Ca 2+在慢性肝病和急性肝损伤的发生和发展中的作用。迄今为止的研究提供的证据表明，TRPM 2介导的Ca 2+进入导致药物诱导的肝脏毒性、缺血再灌注损伤以及非酒精性脂肪肝疾病进展为肝硬化、纤维化和肝细胞癌。目前特别感兴趣的是在ROS增加后肝细胞中TRPM 2激活所涉及的步骤，由细胞内Ca 2+的增加所激活的下游途径，以及这些事件的时间顺序。TRPM 2的这些作用与在心肌和一些其他细胞类型中确定的ROS激活的TRPM 2在促进Ca 2+激活的线粒体ATP合成和细胞存活中的作用之间存在明显的矛盾。姜黄素和其他“天然”化合物对TRPM 2的抑制为抑制ROS诱导的肝细胞损伤提供了一种有吸引力的策略。总之，虽然已经确定ROS引发的TRPM 2激活有助于急性和慢性肝损伤，但需要大量的进一步研究来阐明所涉及的机制，以及TRPM 2的药理学抑制可以成为减少ROS引发的肝损伤的有效临床策略的条件。
TRPM2 channels admit Ca2+ and Na+ across the plasma membrane and release Ca2+ and Zn2+ from lysosomes. Channel activation is initiated by reactive oxygen species (ROS), leading to a subsequent increase in ADP-ribose and the binding of ADP-ribose to an allosteric site in the cytosolic NUDT9 homology domain. In many animal cell types, Ca2+ entry via TRPM2 channels mediates ROS-initiated cell injury and death. The aim of this review is to summarise the current knowledge of the roles of TRPM2 and Ca2+ in the initiation and progression of chronic liver diseases and acute liver injury. Studies to date provide evidence that TRPM2-mediated Ca2+ entry contributes to drug-induced liver toxicity, ischemia–reperfusion injury, and the progression of non-alcoholic fatty liver disease to cirrhosis, fibrosis, and hepatocellular carcinoma. Of particular current interest are the steps involved in the activation of TRPM2 in hepatocytes following an increase in ROS, the downstream pathways activated by the resultant increase in intracellular Ca2+, and the chronology of these events. An apparent contradiction exists between these roles of TRPM2 and the role identified for ROS-activated TRPM2 in heart muscle and in some other cell types in promoting Ca2+-activated mitochondrial ATP synthesis and cell survival. Inhibition of TRPM2 by curcumin and other “natural” compounds offers an attractive strategy for inhibiting ROS-induced liver cell injury. In conclusion, while it has been established that ROS-initiated activation of TRPM2 contributes to both acute and chronic liver injury, considerable further research is needed to elucidate the mechanisms involved, and the conditions under which pharmacological inhibition of TRPM2 can be an effective clinical strategy to reduce ROS-initiated liver injury.
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影响因子：
5.1
作者：
Starkus JG;Poerzgen P;Layugan K;Kawabata KG;Goto JI;Suzuki S;Myers G;Kelly M;Penner R;Fleig A;Horgen FD
通讯作者：
Horgen FD
影响因子：
3.7
作者：
Wang B;Zhang Q;Zhu B;Cui Z;Zhou J
通讯作者：
Zhou J
影响因子：
8.2
作者：
Belrose JC;Jackson MF
通讯作者：
Jackson MF
影响因子：
4.6
作者：
Bao, Lei;Festa, Fernanda;Miller, Barbara A.
通讯作者：
Miller, Barbara A.
影响因子：
3
作者：
Chattopadhyay, Pronobesh;Chaudhury, Pallab;Wahi, Arun Kumar
通讯作者：
Wahi, Arun Kumar