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  • Title: A general anaesthetic propofol inhibits aquaporin-4 in the presence of Zn²⁺.
    Author: Kato J, Hayashi MK, Aizu S, Yukutake Y, Takeda J, Yasui M.
    Journal: Biochem J; 2013 Sep 01; 454(2):275-82. PubMed ID: 23772702.
    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 the modulation 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.
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