Oxidative stress-induced activation of Abl and Src kinases rapidly induces P-glycoprotein internalization via phosphorylation of caveolin-1 on tyrosine-14, decreasing cortisol efflux at the blood–brain barrier
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- Yutaro Hoshi
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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- Yasuo Uchida
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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- Masanori Tachikawa
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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- Sumio Ohtsuki
- Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
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- Pierre-Olivier Couraud
- Institut Cochin, Inserm U1016, CNRS UMR8104, Paris Descartes University, Paris, France
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- Takashi Suzuki
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Japan
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- Tetsuya Terasaki
- Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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説明
<jats:p> Exposure of the brain to high levels of glucocorticoids during ischemia–reperfusion induces neuronal cell death. Oxidative stress alters blood–brain barrier (BBB) function during ischemia–reperfusion, and so we hypothesized that it might impair P-glycoprotein (P-gp)-mediated efflux transport of glucocorticoids at the BBB. Therefore, the purpose of this study was to clarify the molecular mechanism of this putative decrease of P-gp-mediated efflux function. First, we established that H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> treatment of a human in vitro BBB model (hCMEC/D3) reduced both P-gp efflux transport activity and protein expression on the plasma membrane within 20 min. These results suggested that the rapid decrease of efflux function might be due to internalization of P-gp. Furthermore, H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> treatment markedly increased tyrosine-14-phosphorylated caveolin-1, which is involved in P-gp internalization. A brain perfusion study in rats showed that cortisol efflux at the BBB was markedly decreased by H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub> administration, and inhibitors of Abl kinase and Src kinase, which phosphorylate tyrosine-14 in caveolin-1, suppressed this decrease. Overall, these findings support the idea that oxidative stress-induced activation of Abl kinase and Src kinase induces internalization of P-gp via the phosphorylation of tyrosine-14 in caveolin-1, leading to a rapid decrease of P-gp-mediated cortisol efflux at the BBB. </jats:p>
収録刊行物
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- Journal of Cerebral Blood Flow & Metabolism
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Journal of Cerebral Blood Flow & Metabolism 40 (2), 420-436, 2019-01-09
SAGE Publications
