TRPM2 Channel-Mediated ROS-Sensitive Ca2+ Signaling Mechanisms in Immune Cells

Mortadza, Sharifah Alawieyah Syed; Wang, Lu; Li, Dongliang; Jiang, Lin‐Hua

doi:10.3389/fimmu.2015.00407

Cited by 80 publications

(72 citation statements)

References 61 publications

(74 reference statements)

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“…Since TRPM2 is a redox-sensitive channel (Hara et al, 2002;Perraud et al, 2005), a possible mechanism of phagosomal TRPM2 activation may involve generation of oxidants and the subsequent production of ADPR (Hara et al, 2002;Knowles et al, 2013;Perraud et al, 2005;Syed Mortadza et al, 2015;Toth and Csanady, 2010;Wehage et al, 2002). We observed that the H 2 O 2 -activated current in Trpm2 +/+ BMDMs treated with an antagonistic analog of ADPR was reduced to the level seen in Trpm2 −/− BMDMs, suggesting that H 2 O 2 activated phagosomal TRPM2 through ADPR generation.…”

Section: (N=3) *P<005 (T-test) (Fg) Adpr Antagonism Increases Phamentioning

confidence: 66%

“…Transient receptor potential melastatin 2 (TRPM2), a redoxsensitive non-selective cation channel localized in the plasma membrane (Hara et al, 2002;Knowles et al, 2013;Perraud et al, 2001Perraud et al, , 2005Syed Mortadza et al, 2015;Toth and Csanady, 2010), plays an important role in bacterial clearance due in part to its ability to activate cytokine generation (Knowles et al, 2011;Qian et al, 2014). Impaired production of cytokines in Trpm2 −/− mice led to high mortality following Listeria monocytogenes (LM) challenge (Knowles et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages

Kiya

Gong

et al. 2017

Journal of Cell Science

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Acidification of macrophage phagosomes serves an important bactericidal function. We show here that the redox-sensitive transient receptor potential (TRP) cation channel TRPM2 is expressed in the phagosomal membrane and regulates macrophage bactericidal activity through the activation of phagosomal acidification. Measurement of the TRPM2 current in phagosomes identified TRPM2 as a functional redox-sensitive cation channel localized in the phagosomal membrane. Simultaneous measurements of phagosomal Ca 2+ changes and phagosome acidification in macrophages undergoing phagocytosis demonstrated that TRPM2 was required to mediate the efflux of cations and for phagosomal acidification during the process of phagosome maturation. Acidification in phagosomes was significantly reduced in macrophages isolated from Trpm2 −/− mice as compared to wild type, and acidification was coupled to reduced bacterial clearance in Trpm2 −/− mice. Trpm2 +/+ macrophages treated with the vacuolar H + -ATPase inhibitor bafilomycin showed reduced bacterial clearance, similar to that in Trpm2 −/− macrophages. Direct activation of TRPM2 using adenosine diphosphate ribose (ADPR) induced both phagosomal acidification and bacterial killing. These data collectively demonstrate that TRPM2 regulates phagosomal acidification, and is essential for the bacterial killing function of macrophages.

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Section: (N=3) *P<005 (T-test) (Fg) Adpr Antagonism Increases Phamentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages

Kiya

Gong

et al. 2017

Journal of Cell Science

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“…As introduced above, studies over the past years have shown that the Ca 2+ -permeable TRPM2 channel on the cell surface acts as a major molecular mechanism for ROS-induced Ca 2+ signalling in immune cells80. An early study reported that exposure of microglial cells to H 2 O 2 induced an increase in the [Ca 2+ ] c 73 but it was not clearly understood how important the TRPM2 channel was in mediating ROS-induced Ca 2+ signalling.…”

Section: Discussionmentioning

confidence: 99%

Signalling mechanisms mediating Zn2+-induced TRPM2 channel activation and cell death in microglial cells

Mortadza

Sim

Stacey

et al. 2017

Sci Rep

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Excessive Zn2+ causes brain damage via promoting ROS generation. Here we investigated the role of ROS-sensitive TRPM2 channel in H2O2/Zn2+-induced Ca2+ signalling and cell death in microglial cells. H2O2/Zn2+ induced concentration-dependent increases in cytosolic Ca2+ concentration ([Ca2+]c), which was inhibited by PJ34, a PARP inhibitor, and abolished by TRPM2 knockout (TRPM2-KO). Pathological concentrations of H2O2/Zn2+ induced substantial cell death that was inhibited by PJ34 and DPQ, PARP inhibitors, 2-APB, a TRPM2 channel inhibitor, and prevented by TRPM2-KO. Further analysis indicate that Zn2+ induced ROS production, PARP-1 stimulation, increase in the [Ca2+]c and cell death, all of which were suppressed by chelerythrine, a protein kinase C inhibitor, DPI, a NADPH-dependent oxidase (NOX) inhibitor, GKT137831, a NOX1/4 inhibitor, and Phox-I2, a NOX2 inhibitor. Furthermore, Zn2+-induced PARP-1 stimulation, increase in the [Ca2+]c and cell death were inhibited by PF431396, a Ca2+-sensitive PYK2 inhibitor, and U0126, a MEK/ERK inhibitor. Taken together, our study shows PKC/NOX-mediated ROS generation and PARP-1 activation as an important mechanism in Zn2+-induced TRPM2 channel activation and, TRPM2-mediated increase in the [Ca2+]c to trigger the PYK2/MEK/ERK signalling pathway as a positive feedback mechanism that amplifies the TRPM2 channel activation. Activation of these TRPM2-depenent signalling mechanisms ultimately drives Zn2+-induced Ca2+ overloading and cell death.

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“…A role for TRPM2 in ROS-associated cell death has been noted in various cell types including cerebral cortical neurons and myocytes (17, 41). TRPM2 has been linked to inflammasome assembly (42) and ischemia-reperfusion–induced cellular injury (43).…”

Section: Discussionmentioning

confidence: 99%

Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway

et al. 2017

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Store-operated Ca2+ entry (SOCE) is critical for salivary gland fluid secretion. We report that radiation treatment caused persistent salivary gland dysfunction by activating a TRPM2-dependent mitochondrial pathway, leading to caspase-3–mediated cleavage of stromal interaction molecule 1 (STIM1) and loss of SOCE. After irradiation, acinar cells from the submandibular glands of TRPM2+/+, but not those from TRPM2−/− mice, displayed an increase in the concentrations of mitochondrial Ca2+ and reactive oxygen species, a decrease in mitochondrial membrane potential, and activation of caspase-3, which was associated with a sustained decrease in STIM1 abundance and attenuation of SOCE. In a salivary gland cell line, silencing the mitochondrial Ca2+ uniporter or caspase-3 or treatment with inhibitors of TRPM2 or caspase-3 prevented irradiation-induced loss of STIM1 and SOCE. Expression of exogenous STIM1 in the salivary glands of irradiated mice increased SOCE and fluid secretion. We suggest that targeting the mechanisms underlying the loss of STIM1 would be a potentially useful approach for preserving salivary gland function after radiation therapy.

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TRPM2 Channel-Mediated ROS-Sensitive Ca2+ Signaling Mechanisms in Immune Cells

Cited by 80 publications

References 61 publications

Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages

Role of the phagosomal redox-sensitive TRP channel TRPM2 in regulating bactericidal activity of macrophages

Signalling mechanisms mediating Zn2+-induced TRPM2 channel activation and cell death in microglial cells

Radiation inhibits salivary gland function by promoting STIM1 cleavage by caspase-3 and loss of SOCE through a TRPM2-dependent pathway

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