A general anaesthetic propofol inhibits aquaporin-4 in the presence of Zn2+

Jungo Kato, Mariko Kato Hayashi, Shinnosuke Aizu, Yoshinori Yukutake, Junzo Takeda, Masato Yasui

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16 Citations (Scopus)

Abstract

AQP4 (aquaporin-4), a water channel protein that is predominantly expressed in astrocyte end-feet, plays an important role in the brain oedema formation, and is thereby considered to be a potential therapeutic target. Using a stopped-flow analysis, we showed that propofol (2,6-diisopropylphenol), a general anaesthetic drug, profoundly inhibited the osmotic water permeability of AQP4 proteoliposomes in the presence of Zn2+ . This propofol inhibition was not observed in AQP1, suggesting the specificity for AQP4. In addition, the inhibitory effects of propofol could be reversed by the removal of Zn2+ . Other lipid membrane fluidizers also similarly inhibited AQP4, suggesting that themodulation of protein-lipid interactions plays an essential role in the propofol-induced inhibition of AQP4. Accordingly, we used Blue native PAGE and showed that the profound inhibition caused by propofol in the presence of Zn2+ is coupled with the reversible clustering of AQP4 tetramers. Site-directed mutagenesis identified that Cys253, located at the membrane interface connecting to the C-terminal tail, is responsible for Zn2+ -mediated propofol inhibition. Overall, we discovered that propofol specifically and reversibly inhibits AQP4 through the interaction between Zn2+ and Cys253. The findings provide new insight into the functional regulation of AQP4 and may facilitate the identification of novel AQP4-specific inhibitors.

Original languageEnglish
Pages (from-to)275-282
Number of pages8
JournalBiochemical Journal
Volume454
Issue number2
DOIs
Publication statusPublished - 2013 Sep 1

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Keywords

  • Aquaporin 4 (AQP4)
  • Brain oedema
  • General anaesthetic
  • Water channel

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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