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- W2018804582 abstract "Although various cytotoxic effects on neuronal cells caused by methamphetamine (METH) have been investigated, the cellular and molecular mechanisms of METH-induced neurotoxicity remain to be elucidated. We previously reported that METH-induced cytomorphological effects on retinoic acid (RA)-differentiated SH-SY5Y human neuroblastoma cells involved macropinocytosis, which is an actin-dependent endocytic pathway. We also noted that hyperstimulation of this process might play an important role in the cytotoxicity of METH in neuronal cells. In this study, we investigated the molecular mechanisms as well as subsequent outcomes of macropinocytosis during METH treatment. It was found that macropinosomes formed upon exposure to METH were colocalized with constitutively active GFP-Ras (G12V) and GFP-Rac1 (Q61L). Furthermore, both Ras inhibitor, farnesylthiosalicylic acid (FTS), and Rac1 inhibitor, EHT1864, significantly inhibited the formation of macropinosomes, suggesting the involvement of these molecules. The expressions of lysosome-associated membrane proteins (lamps) gradually increased by METH in a time-dependent manner. In contrast, the proteolytic activation of cathepsin L, a marker of lysosomal function, was markedly suppressed by METH. METH-induced dysfunction of lysosomal enzyme as well as cell death was significantly attenuated by nocodazole, a microtube interfering reagent that inhibits the transport of vesicles, including macropinosome, to lysosomes. Our results indicate that METH has cytotoxic effects, at least in part, by inhibiting normal lysosomal function through Ras- and Rac1-mediated macropinocytosis in RA-differentiated SH-SY5Y cells." @default.
- W2018804582 created "2016-06-24" @default.
- W2018804582 creator A5011175612 @default.
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- W2018804582 creator A5052309166 @default.
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- W2018804582 creator A5078155870 @default.
- W2018804582 date "2012-07-01" @default.
- W2018804582 modified "2023-09-25" @default.
- W2018804582 title "Hyperstimulation of macropinocytosis leads to lysosomal dysfunction during exposure to methamphetamine in SH-SY5Y cells" @default.
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- W2018804582 doi "https://doi.org/10.1016/j.brainres.2012.05.017" @default.
- W2018804582 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22613348" @default.
- W2018804582 hasPublicationYear "2012" @default.
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