Lys1110 of TRPM2 is critical for channel activation

Kim, Taek Keun; Nam, Joo Hyun; Ahn, Won Gyun; Kim, Nam Ho; Ham, Hwa Yong; Hong, Chang-Won; Nam, Ju Suk; Lee, Jong-Ho; Huh, Sung‐Oh; So, Insuk; Kim, Sung Joon; Song, Dong Keun

doi:10.1042/bj20130303

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…For confirming the patch-clamp results in the mpkCCD c14 cells, the analyses were repeated in the HEK293 cells. It is well known that HEK293 cells do not express TRPM2 22,23 . We observed that ADPR did not induce TRPM2 channel current in the absence of TRPM2 channel in the HEK293 cell line (Fig.…”

Section: Resultsmentioning

confidence: 99%

Albumin evokes Ca2+-induced cell oxidative stress and apoptosis through TRPM2 channel in renal collecting duct cells reduced by curcumin

Nazıroğlu

Çiğ

Yazğan

et al. 2019

Sci Rep

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In proteinuric nephropathies of chronic kidney disease, the epithelial cells of the nephron including the collecting duct are exposed to high concentrations of luminal albumin. Albumin is taken up from collecting duct cells by endocytosis causing excessive reactive oxygen species (ROS) production and a proinflammatory response. Curcumin used in the traditional medicine possesses anti-inflammatory and antioxidant effects. ROS and ADP-ribose (ADPR) activate the cation channel TRPM2. We hypothesize, that albumin-induced cell stress and proinflammatory response are mediated by Ca 2+ and can be reduced by curcumin. The cortical collecting duct (CCD) cells mpkCCD c14 exhibit spontaneous and inducible Ca 2+ oscillations, which can be blocked by pre-treatment with curcumin. Curcumin accumulates in plasma membrane and intracellular vesicles, where it interferes with TRPM2 and decreases the influx of Ca 2+ . Albumin reduces cell viability and increases apoptosis, NF-κB activation, and mitochondrial membrane depolarization via Ca 2+ -dependent signaling, which results in increased ROS production. Albumin-induced cell stress is diminished by the inhibition of TRPM2 after administration of curcumin and ADPR (PARP1) inhibitors. Curcumin did not reduce the Ca2+ elevation induced by thapsigargin in Ca 2+ -free medium, but it reduced the function of store-operated Ca 2+ channels and ATP-evoked Ca 2+ response. In conclusion, albumin-induced oxidative stress is mediated by Ca 2+ -dependent signaling via TRPM2 and leads to cell damage and a proinflammatory response, strengthening the role of CCD cells in the progression of chronic kidney disease.

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Section: Resultsmentioning

confidence: 99%

Albumin evokes Ca2+-induced cell oxidative stress and apoptosis through TRPM2 channel in renal collecting duct cells reduced by curcumin

Nazıroğlu

Çiğ

Yazğan

et al. 2019

Sci Rep

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“…Accumulating evidence suggests that H 2 O 2 can activate TRPM2 channel either directly or indirectly. 28 It has been postulated that the activation of TRPM2 channel by oxidative stress is triggered via ADP-ribose production (Citation). Mitochondria are a major source of ADP-ribose.…”

Section: Discussionmentioning

confidence: 99%

<p>Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation</p>

Qi¹,

Liu²,

Gao³

et al. 2019

DMSO

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Purpose: Oxidative stress plays an important role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). TRPM2 ion channel functions as a molecular sensor for oxidative stress. The aim of this study was to examine the protective effects of Salidroside, a powerful antioxidative plant, on TRPM2 in an established in vitro model of NAFLD. Methods: NAFLD model was established by palmitic acid (PA) in hepatic L02 cell lines and was added to the media at a final concentration of 400 μM. Cells were used as normal group, PA group and PA receiving varied concentrations of Salidroside (75μg/mL, 150μg/ mL, 300μg/mL). After treating 24 hrs, MTT assay was used to detect cell viability, and ALT level was measured using an appropriate kit assay. Intracellular lipid accumulation was observed by Oil red O staining. Cytosolic Ca 2+ concentrations were evaluated by flow cytometer with Fluo-3/AM. Quantitative RT-PCR was used to measure the mRNA expression of TRPM2, IL-1β and IL-6, and the protein expressions of TRPM2, p-CaMKII and autophagy (LC3B, p62) were determined using Western blot. Results: Treatment with Salidroside effectively restored liver injury and alleviated lipid droplet deposition in a dose-dependent manner, which was associated with inhibition of TRPM2/Ca 2+ /CaMKII pathway. Additionally, autophagic clearance was enhanced by intervention with Salidroside in a dose-dependent manner. Further investigation indicated that Salidroside down-regulated the mRNA expression of IL-1β and IL-6-pro-inflammatory cytokines. Conclusion: These results suggest that Salidroside could alleviate inflammatory injury and steatosis via autophagy activation mediated by downregulation of the TRPM2/Ca 2+ /CaMKII pathway. Targeting the TRPM2 ion channel is a novel treatment strategy for oxidative stressinduced liver in NAFLD.

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“…It is also interesting to note that the distribution of Orai1 amongst the liver subcellular fractions is quite different from that of TRPM2. It is thought that TRPM2 principally functions at the PM, but may also be present in lysosomes, and is also likely to be trafficked to and from the PM [67,68].…”

Section: Discussionmentioning

confidence: 99%

Evidence for the interaction of peroxiredoxin-4 with the store-operated calcium channel activator STIM1 in liver cells

et al. 2018

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Ca entry through store-operated Ca channels (SOCs) in the plasma membrane (PM) of hepatocytes plays a central role in the hormonal regulation of liver metabolism. SOCs are composed of Orai1, the channel pore protein, and STIM1, the activator protein, and are regulated by hormones and reactive oxygen species (ROS). In addition to Orai1, STIM1 also interacts with several other intracellular proteins. Most previous studies of the cellular functions of Orai1 and STIM1 have employed immortalised cells in culture expressing ectopic proteins tagged with a fluorescent polypeptide such as GFP. Little is known about the intracellular distributions of endogenous Orai1 and STIM1. The aims are to determine the intracellular distribution of endogenous Orai1 and STIM1 in hepatocytes and to identify novel STIM1 binding proteins. Subcellular fractions of rat liver were prepared by homogenisation and differential centrifugation. Orai1 and STIM1 were identified and quantified by western blot. Orai1 was found in the PM (0.03%), heavy (44%) and light (27%) microsomal fractions, and STIM1 in the PM (0.09%), and heavy (85%) and light (13%) microsomal fractions. Immunoprecipitation of STIM1 followed by LC/MS or western blot identified peroxiredoxin-4 (Prx-4) as a potential STIM1 binding protein. Prx-4 was found principally in the heavy microsomal fraction. Knockdown of Prx-4 using siRNA, or inhibition of Prx-4 using conoidin A, did not affect Ca entry through SOCs but rendered SOCs susceptible to inhibition by HO. It is concluded that, in hepatocytes, a considerable proportion of endogenous Orai1 and STIM1 is located in the rough ER. In the rough ER, STIM1 interacts with Prx-4, and this interaction may contribute to the regulation by ROS of STIM1 and SOCs.

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Lys1110 of TRPM2 is critical for channel activation

Cited by 5 publications

References 46 publications

Albumin evokes Ca2+-induced cell oxidative stress and apoptosis through TRPM2 channel in renal collecting duct cells reduced by curcumin

Albumin evokes Ca2+-induced cell oxidative stress and apoptosis through TRPM2 channel in renal collecting duct cells reduced by curcumin

<p>Salidroside-Mitigated Inflammatory Injury of Hepatocytes with Non-Alcoholic Fatty Liver Disease via Inhibition TRPM2 Ion Channel Activation</p>

Evidence for the interaction of peroxiredoxin-4 with the store-operated calcium channel activator STIM1 in liver cells

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