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

Yutaro Hoshi, Yasuo Uchida, Masanori Tachikawa, Sumio Ohtsuki, Pierre Olivier Couraud, Takashi Suzuki, Tetsuya Terasaki

研究成果: Article査読

10 被引用数 (Scopus)

抄録

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 H2O2 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, H2O2 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 H2O2 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.

本文言語English
ページ(範囲)420-436
ページ数17
ジャーナルJournal of Cerebral Blood Flow and Metabolism
40
2
DOI
出版ステータスPublished - 2020 2 1

ASJC Scopus subject areas

  • 神経学
  • 臨床神経学
  • 循環器および心血管医学

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