Journal
BIOCHEMICAL JOURNAL
Volume 454, Issue -, Pages 275-282Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20130046
Keywords
aquaporin 4 (AQP4); brain oedema; general anaesthetic; water channel
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Funding
- Global Centers of Excellence Program for Human Metabolic System Biology of the Ministry of Education, Culture, Sports, Science and Technology Japan
- Program for the Advancement of Next Generation Research Project of Keio University
- Japan New Energy and Industrial Technology Development Organization (NEDO) [P08005]
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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 Cys(253), 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 Cys(253). 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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