TRPM2 promotes autophagic degradation in vascular smooth muscle cells

Zhao, Qiannan; Li, Jingxuan; Ko, Wing‐Hung; Kwan, Yiu Wa; Jiang, Liwen; Sun, Lei; Yao, Xiaoqiang

doi:10.1038/s41598-020-77620-y

Cited by 17 publications

(17 citation statements)

References 28 publications

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“…TRPM2 proteins have been detected in lysosomes in several cell types [ 50 , 51 , 52 , 53 , 54 ]. These include pancreatic ß-cells, neuronal cells, dendritic cells, macrophages, and vascular smooth muscle cells.…”

Section: Trpm2 Non-selective Cation Channels Are Formed From Tetramers Of the Trpm2 Polypeptide Principally In The Plasma Membrane And Lymentioning

confidence: 99%

“…In vascular smooth muscle cells and in macrophages, Ca 2+ release via TRPM2 channels is proposed to increase lysosomal acidification, leading to enhanced autosomal degradation. This, in turn, is proposed to lead to cell death in smooth muscle cells and to be responsible for bactericidal activity in macrophages [ 50 , 51 ].…”

Section: Trpm2 Non-selective Cation Channels Are Formed From Tetramers Of the Trpm2 Polypeptide Principally In The Plasma Membrane And Lymentioning

confidence: 99%

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TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

2021

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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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Section: Trpm2 Non-selective Cation Channels Are Formed From Tetramers Of the Trpm2 Polypeptide Principally In The Plasma Membrane And Lymentioning

confidence: 99%

Section: Trpm2 Non-selective Cation Channels Are Formed From Tetramers Of the Trpm2 Polypeptide Principally In The Plasma Membrane And Lymentioning

confidence: 99%

TRPM2 Non-Selective Cation Channels in Liver Injury Mediated by Reactive Oxygen Species

2021

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“…It is also worth mentioning that TRPM2 may contribute to the type II programmed cell death called autophagy. Although no reports are showing TRPM2 involvement in autophagy induction in endothelial cells, there is evidence of its participation in this type of cell death in vascular smooth muscles and brain pericyte injury [11,39]. In primary cultured mouse aortic smooth muscle cells (mASMCs) TRPM2 expression was found in lysosomes/autolysosomes resulting from nutrients starvation.…”

Section: Trpm2 In Endothelial Cell Deathmentioning

confidence: 99%

“…In primary cultured mouse aortic smooth muscle cells (mASMCs) TRPM2 expression was found in lysosomes/autolysosomes resulting from nutrients starvation. Both autophagic response and lysosomal/autolysosomal acidification were reduced after TRPM2 knockout [11]. In turn, in the human brain vascular pericytes, zinc oxide nanoparticles (ZnO-NP)-induced autophagy was accompanied by increased TRPM2-S expression.…”

Section: Trpm2 In Endothelial Cell Deathmentioning

confidence: 99%

“…TRPM2 channel activity was so far connected with such events as a cellular response to ischemia-reperfusion injury, regulation of endothelial permeability, inflammation, development of cancer and degenerative diseases, or induction of cell death, including apoptosis and autophagy [2,[7][8][9][10][11]. In the context of the endothelial layer, the impact of TRPM2 activation on barrier function, apoptosis, cell migration, angiogenesis, and transendothelial migration of the leukocytes seems to be particularly interesting.…”

Section: Introductionmentioning

confidence: 99%

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The Role of TRPM2 in Endothelial Function and Dysfunction

Zielińska

Zabrzyński

Gagat

et al. 2021

IJMS

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The transient receptor potential (TRP) melastatin-like subfamily member 2 (TRPM2) is a non-selective calcium-permeable cation channel. It is expressed by many mammalian tissues, including bone marrow, spleen, lungs, heart, liver, neutrophils, and endothelial cells. The best-known mechanism of TRPM2 activation is related to the binding of ADP-ribose to the nudix-box sequence motif (NUDT9-H) in the C-terminal domain of the channel. In cells, the production of ADP-ribose is a result of increased oxidative stress. In the context of endothelial function, TRPM2-dependent calcium influx seems to be particularly interesting as it participates in the regulation of barrier function, cell death, cell migration, and angiogenesis. Any impairments of these functions may result in endothelial dysfunction observed in such conditions as atherosclerosis or hypertension. Thus, TRPM2 seems to be an attractive therapeutic target for the conditions connected with the increased production of reactive oxygen species. However, before the application of TRPM2 inhibitors will be possible, some issues need to be resolved. The main issues are the lack of specificity, poor membrane permeabilization, and low stability in in vivo conditions. The article aims to summarize the latest findings on a role of TRPM2 in endothelial cells. We also show some future perspectives for the application of TRPM2 inhibitors in cardiovascular system diseases.

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TRPM2‐dependent autophagy inhibition exacerbates oxidative stress‐induced CXCL16 secretion by keratinocytes in vitiligo

Kang,

Wang,

Chen

et al. 2024

The Journal of Pathology

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Vitiligo is a depigmented skin disease due to the destruction of melanocytes. Under oxidative stress, keratinocyte‐derived chemokine C‐X‐C motif ligand 16 (CXCL16) plays a critical role in recruiting CD8+ T cells, which kill melanocytes. Autophagy serves as a protective cell survival mechanism and impairment of autophagy has been linked to increased secretion of the proinflammatory cytokines. However, the role of autophagy in the secretion of CXCL16 under oxidative stress has not been investigated. Herein, we initially found that autophagy was suppressed in both keratinocytes of vitiligo lesions and keratinocytes exposed to oxidative stress in vitro. Autophagy inhibition also promoted CXCL16 secretion. Furthermore, upregulated transient receptor potential cation channel subfamily M member 2 (TRPM2) functioned as an upstream oxidative stress sensor to inhibit autophagy. Moreover, TRPM2‐mediated Ca2+ influx activated calpain to shear autophagy related 5 (Atg5) and Atg12–Atg5 conjugate formation was blocked to inhibit autophagy under oxidative stress. More importantly, Atg5 downregulation enhanced the binding of interferon regulatory factor 3 (IRF3) to the CXCL16 promoter region by activating Tank‐binding kinase 1 (TBK1), thus promoting CXCL16 secretion. These findings suggested that TRPM2‐restrained autophagy promotes CXCL16 secretion via the Atg5‐TBK1‐IRF3 signaling pathway under oxidative stress. Inhibition of TRPM2 may serve as a potential target for the treatment of vitiligo. © 2024 The Pathological Society of Great Britain and Ireland.

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TRPM2 promotes autophagic degradation in vascular smooth muscle cells

Cited by 17 publications

References 28 publications

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

The Role of TRPM2 in Endothelial Function and Dysfunction

TRPM2‐dependent autophagy inhibition exacerbates oxidative stress‐induced CXCL16 secretion by keratinocytes in vitiligo

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