Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition

Ishida, Kazuyuki; Aoki, Kaori; Takishita, Tomoko; Miyara, Masatsugu; Sakamoto, Shuichiro; Sanoh, Seigo; Kimura, Toshikiro; Kanda, Yasunari; Ohta, Shigeru; Kotake, Yaichiro

doi:10.3390/ijms18081754

Cited by 7 publications

(5 citation statements)

References 48 publications

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“…The following procedures were performed under sterile conditions. Primary neuronal culture was performed as previously described 28) with some modifications. The prefrontal part of the cerebral cortex was dissected from fetal Slc:Wistar/ST rats at gestation day 18, and the cells were dissociated by gentle pipetting and plated onto culture plates at a density of 3 × 10 5 cells/cm 2 .…”

Section: Methodsmentioning

confidence: 99%

Methylmercury Decreases AMPA Receptor Subunit GluA2 Levels in Cultured Rat Cortical Neurons

Ishida

Takeda

Takehara

et al. 2023

Biological & Pharmaceutical Bulletin

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Methylmercury (MeHg) is a well-known environmental pollutant that has harmful effects on the central nervous systems of humans and animals. The molecular mechanisms of MeHg-induced neurotoxicity at low concentrations are not fully understood. Here, we investigated the effects of low-concentration MeHg on the cell viability, Ca 2 homeostasis, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA2 levels, which determine Ca 2 permeability of AMPA receptors, in rat primary cortical neurons. Exposure of cortical neurons to 100 and 300 nM MeHg for 7 d resulted in a decrease in GluA2 levels, an increase in basal intracellular Ca 2 concentration, increased phosphorylation levels of extracellular signal-regulated kinase (ERK)1/2 and p38, and decreased cell viability. Moreover, glutamate stimulation exacerbated the decrease in cell viability and increased intracellular Ca 2 levels in MeHg-treated neurons compared to control neurons. MeHg-induced neuronal cell death was ameliorated by 1-naphthyl acetyl spermine, a specific antagonist of Ca 2 -permeable, GluA2-lacking AMPA receptors. Our findings raise the possibility that decreased neuronal GluA2 levels and the subsequent increase in intracellular Ca 2 concentration may contribute to MeHg-induced neurotoxicity.

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Section: Methodsmentioning

confidence: 99%

Methylmercury Decreases AMPA Receptor Subunit GluA2 Levels in Cultured Rat Cortical Neurons

Ishida

Takeda

Takehara

et al. 2023

Biological & Pharmaceutical Bulletin

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“…Nucleocytoplasmic fractionation was performed based on prior studies (Yabuki et al 2021;Ishida et al, 2017) with a few modifications.…”

Section: Nucleocytoplasmic Fractionationmentioning

confidence: 99%

Tributyltin activates the Keap1–Nrf2 pathway via a macroautophagy-independent reduction in Keap1

et al. 2023

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Tributyltin (TBT) is an environmental chemical, which was used as an antifouling agent for ships. Although its use has been banned, it is still persistently present in ocean sediments. Although TBT reportedly causes various toxicity in mammals, few studies on the mechanisms of biological response against TBT toxicity exist. The well-established Keap1-Nrf2 pathway is activated as a cytoprotective mechanism under stressful conditions. The relationship between TBT and the Keap1-Nrf2 pathway remains unclear. In the present study, we evaluated the effect of TBT on the Keap1-Nrf2 pathway. TBT reduced Keap1 protein expression in Neuro2a cells, a mouse neuroblastoma cell line, after 6 hr without altering mRNA expression levels. TBT also promoted the nuclear translocation of Nrf2, a transcription factor for antioxidant proteins, after 12 hr and augmented the expression of heme oxygenase 1, a downstream protein of Nrf2. Furthermore, TBT decreased Keap1 levels in mouse embryonic fibroblast (MEF) cells, with the knockout of Atg5, which is essential for macroautophagy, as well as in wild-type MEF cells. These results suggest that TBT activates the Keap1-Nrf2 pathway via the reduction in the Keap1 protein level in a macroautophagy-independent manner. The Keap1-Nrf2 pathway is activated by conformational changes in Keap1 induced by reactive oxygen species or electrophiles. Furthermore, any unutilized Keap1 protein is degraded by macroautophagy. Understanding the novel mechanism governing the macroautophagy-independent reduction in Keap1 by TBT may provide insights into the unresolved biological response mechanism against TBT toxicity and the activation mechanism of the Keap1-Nrf2 pathway.

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“…Nucleocytoplasmic fractionation was performed as described by Ishida et al (2017), with minor modifications. HeLa cells were seeded in 100-mm dishes and incubated overnight at 37°C in a humidified 5%-CO 2 incubator.…”

Section: Nucleocytoplasmic Fractionationmentioning

confidence: 99%

MiT/TFE family members suppress L-leucyl–L-leucine methyl ester-induced cell death

et al. 2021

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Lysosomes are degradative organelles essential for cell homeostasis. However, various internal and external stimuli, including L-leucyl-L-leucine methyl ester (LLOMe), which is one of the common lysosomotropic agents, permeabilize the lysosomal membrane, leading to lysosome-dependent cell death because of leakage of lysosomal contents to the cytosol. The microphthalmia/transcription factor E (MiT/TFE) family members, which include transcription factor EB (TFEB), transcription factor E3 (TFE3), and microphthalmia-associated transcription factor (MITF), are master regulators of lysosomal biogenesis and are known to be involved in the lysosomal stress response. However, their protective effects against cell death associated with lysosomal-membrane damage are still poorly understood. In this study, we confirmed that LLOMe-induced lysosomal damage triggered nuclear translocation of TFEB/ TFE3/MITF and increased the mRNA levels of their target genes encoding lysosomal hydrolases and lysosomal membrane proteins in HeLa cells. Furthermore, we revealed that TFEB/TFE3/MITF knockdown exacerbated LLOMe-induced cell death. However, TFEB overexpression only slightly attenuated LLOMe-induced cell death, despite enhanced LLOMe-induced increase in CTSD mRNA levels, implying that the endogenous levels of MiT/TFE family members might be sufficient to promote lysosomal biogenesis in response to lysosomal-membrane damage. Our results suggest that MiT/TFE family members suppress the cell death associated with lysosomal-membrane damage.

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Low-Concentration Tributyltin Decreases GluR2 Expression via Nuclear Respiratory Factor-1 Inhibition

Cited by 7 publications

References 48 publications

Methylmercury Decreases AMPA Receptor Subunit GluA2 Levels in Cultured Rat Cortical Neurons

Methylmercury Decreases AMPA Receptor Subunit GluA2 Levels in Cultured Rat Cortical Neurons

Tributyltin activates the Keap1–Nrf2 pathway via a macroautophagy-independent reduction in Keap1

MiT/TFE family members suppress L-leucyl–L-leucine methyl ester-induced cell death

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