Miller Barbara A, Cheung Joseph Y
Departments of Pediatrics and Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA.
Center of Translational Medicine and Department of Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA.
J Physiol. 2016 Aug 1;594(15):4181-91. doi: 10.1113/JP270934. Epub 2015 Nov 11.
TRPM channels are a subgroup of the transient receptor potential (TRP) channel superfamily whose members have important roles in cell proliferation and survival. TRPM2, the second subfamily member to be cloned, is expressed in many tissues including brain, heart, vasculature and haematopoietic cells. TRPM2 is activated by oxidative stress and several other extracellular signals including tumour necrosis factor α (TNF-α) and amyloid β-peptide, which increase production of ADP-ribose (ADPR). ADPR binds to the TRPM2 C-terminal NUDT9-H domain, activating the channel. Early studies support the paradigm that TRPM2 activation induces cell death by sustained Ca(2+) influx or by enhancing cytokine production, aggravating inflammation and tissue injury. However, more recent data show that for a number of physiological processes, TRPM2 is protective. TRPM2 protects lungs from endotoxin-induced injury by reducing reactive oxygen species (ROS) production by phagocytes. It protects hearts from oxidative damage after ischaemia-reperfusion or hypoxia-reoxygenation by maintaining better mitochondrial bioenergetics and by decreasing ROS. Sustained Ca(2+) entry through TRPM2 is required to maintain cellular bioenergetics and protect against hypoxia-reoxygenation injury. TRPM2 also protects neuroblastoma from moderate oxidative stress by decreasing ROS through increased levels of forkhead box transcription factor 3a (FOXO3a) and a downstream effector, superoxide dismutase 2. TRPM2 is important for tumour growth and cell survival through modulation of hypoxia-inducible transcription factor expression, mitochondrial function and mitophagy. These findings in cardiac ischaemia and in neuroblastoma suggest that TRPM2 has a basic role in sustaining mitochondrial function and in cell survival that applies to a number of physiological systems and pathophysiological processes including ischaemia-reperfusion injury.
瞬时受体电位（TRP）通道超家族中的TRPM通道亚群，其成员在细胞增殖和存活中发挥重要作用。TRPM2是第二个被克隆的亚家族成员，在包括脑、心脏、血管和造血细胞在内的许多组织中表达。TRPM2可被氧化应激以及包括肿瘤坏死因子α（TNF-α）和淀粉样β肽在内的其他几种细胞外信号激活，这些信号会增加二磷酸腺苷核糖（ADPR）的产生。ADPR与TRPM2的C末端NUDT9-H结构域结合，激活该通道。早期研究支持这样的范式，即TRPM2激活通过持续的Ca(2+)内流或通过增强细胞因子产生、加重炎症和组织损伤来诱导细胞死亡。然而，最近的数据表明，在许多生理过程中，TRPM2具有保护作用。TRPM2通过减少吞噬细胞产生的活性氧（ROS）来保护肺部免受内毒素诱导的损伤。它通过维持更好的线粒体生物能量学并减少ROS来保护心脏免受缺血再灌注或缺氧复氧后的氧化损伤。通过TRPM2持续的Ca(2+)内流是维持细胞生物能量学和防止缺氧复氧损伤所必需的。TRPM2还通过增加叉头框转录因子3a（FOXO3a）和下游效应物超氧化物歧化酶2的水平来减少ROS，从而保护神经母细胞瘤免受中度氧化应激。TRPM2通过调节缺氧诱导转录因子表达、线粒体功能和线粒体自噬，对肿瘤生长和细胞存活很重要。在心脏缺血和神经母细胞瘤中的这些发现表明，TRPM2在维持线粒体功能和细胞存活方面具有基本作用，这适用于包括缺血再灌注损伤在内的许多生理系统和病理生理过程。
