Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2′-phosphate

Tóth, Balázs; Iordanov, I; Csanády, László

doi:10.1085/jgp.201511377

Cited by 56 publications

(62 citation statements)

References 34 publications

(112 reference statements)

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“…Oxidative stress, TNF␣, and amyloid ␤-peptide are among the key extracellular signals known to activate TRPM2 (10 -13). Stimulation with these extracellular signals results in production of adenosine diphosphate-ribose (ADPR), which activates the channel by binding to the TRPM2 C-terminal NUDT9-H domain (7,(13)(14)(15)(16)(17)(18)(19). A rise in intracellular Ca 2ϩ and calmodulin also positively regulate TRPM2 (20 -22), and acidification can inhibit channel activity (23)(24)(25).…”

Section: Transient Receptor Potential (Trp)mentioning

confidence: 99%

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Bao

Chen

Conrad

et al. 2016

Journal of Biological Chemistry

113

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Edited by Xiao-Fan WangTransient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in modulating cell survival following oxidant injury and is highly expressed in many cancers including neuroblastoma. Here, in xenografts generated from neuroblastoma cells in which TRPM2 was depleted with CRISPR/Cas9 technology and in in vitro experiments, tumor growth was significantly inhibited and doxorubicin sensitivity increased. The hypoxia-inducible transcription factor 1/2␣ (HIF-1/2␣) signaling cascade including proteins involved in oxidant stress, glycolysis, and mitochondrial function was suppressed by TRPM2 depletion. TRPM2-depleted SH-SY5Y neuroblastoma cells demonstrated reduced oxygen consumption and ATP production after doxorubicin, confirming impaired cellular bioenergetics. In cells in which TRPM2 was depleted, mitochondrial superoxide production was significantly increased, particularly following doxorubicin. Ectopic expression of superoxide dismutase 2 (SOD2) reduced ROS and preserved viability of TRPM2-depleted cells, however, failed to restore ATP levels. Mitochondrial reactive oxygen species (ROS) were also significantly increased in cells in which TRPM2 function was inhibited by TRPM2-S, and pretreatment of these cells with the antioxidant MitoTEMPO significantly reduced ROS levels in response to doxorubicin and protected cell viability. Expression of the TRPM2 pore mutant E960D, in which calcium entry through TRPM2 is abolished, also resulted in significantly increased mitochondrial ROS following doxorubicin treatment, showing the critical role of TRPM2-mediated calcium entry. These findings demonstrate the important function of TRPM2 in modulation of cell survival through mitochondrial ROS, and the potential of targeted inhibition of TRPM2 as a therapeutic approach to reduce cellular bioenergetics, tumor growth, and enhance susceptibility to chemotherapeutic agents.

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Section: Transient Receptor Potential (Trp)mentioning

confidence: 99%

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Bao

Chen

Conrad

et al. 2016

Journal of Biological Chemistry

113

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“…Importantly, these activating signals are linked to the cellular redox state (Heiner et al, 2003). Other studies have also indicated that NAD or H 2 O 2 may not activate TRPM2 directly (Buelow et al, 2008; Perraud et al, 2005; Toth and Csanady, 2010; Toth et al, 2015). Here, we addressed the role of the ROS-sensing function of TRPM2 in regulating neutrophil migration.…”

Section: Introductionmentioning

confidence: 99%

Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation

et al. 2016

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SUMMARY Blood neutrophils perform an essential host-defense function by directly migrating to bacterial invasion sites to kill bacteria. The mechanisms mediating the transition from the migratory to bactericidal phenotype remain elusive. Here, we demonstrate that TRPM2, a trp superfamily member, senses neutrophil-generated reactive oxygen species and restrains neutrophil migration. The inhibitory function of oxidant sensing by TRPM2 requires the oxidation of Cys549, which then induces TRMP2 binding to formyl peptide receptor 1 (FPR1) and subsequent FPR1 internalization and signaling inhibition. The oxidant sensing-induced termination of neutrophil migration at the site of infection permits a smooth transition to the subsequent microbial killing phase.

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“…TRPM2 is a Ca 2+ -permeable channel gated by ADPR, ADPR-2′-phosphate (ADPRP), and Ca 2+ (Toth et al, 2015). In addition to acting as a channel on the plasma membrane, TRPM2 is also functional as a lysosomal channel in pancreatic β-cells and dendritic cells.…”

Section: Lysosomal Calcium Homeostasismentioning

confidence: 99%

Lysosomal Calcium in Neurodegeneration

Feng

2016

messenger

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Lysosomes are the central organelles responsible for macromolecule recycling in the cell. Lysosomal dysfunction is the primary cause of lysosomal storage diseases (LSDs), and contributes significantly to the pathogenesis of common neurodegenerative diseases. The lysosomes are also intracellular stores for calcium ions, one of the most common second messenger in the cell. Lysosomal Ca2+ is required for diverse cellular processes including signal transduction, vesicular trafficking, autophagy, nutrient sensing, exocytosis, and membrane repair. In this review, we first summarize some recent progresses in the studies of lysosome Ca2+ regulation, with a focus on the newly discovered lysosomal Ca2+ channels and the mechanisms of lysosomal Ca2+ store refilling. We then discuss how defects in lysosomal Ca2+ release and store maintenance cause lysosomal dysfunction and neurodegeneration.

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Ruling out pyridine dinucleotides as true TRPM2 channel activators reveals novel direct agonist ADP-ribose-2′-phosphate

Abstract: ADP-ribose-2′-phosphate acts as a direct agonist of TRPM2, whereas NAD, NAAD, and NAADP do not.

Cited by 56 publications

References 34 publications

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Oxidant Sensing by TRPM2 Inhibits Neutrophil Migration and Mitigates Inflammation

Lysosomal Calcium in Neurodegeneration

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