A general anesthetic propofol inhibits aquaporin-4 in the presence of Zn2{+}

Aquaporin-4 (AQP4), a water channel protein that is predominantly expressed in astrocyte end-feet, plays an important role in the brain edema formation, thereby considered to be a potential therapeutic target. Using a stopped-flow analysis, we showed that propofol (2,6-diisopropylphenol), a general anesthetic 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+ ion. 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. These findings provide new insight into the functional regulation of AQP4 and may facilitate the identification of novel AQP4-specific inhibitors.
Source: BJ Cell - Category: Biochemistry Authors: Tags: BJ Cell Source Type: research