A general anaesthetic propofol inhibits aquaporin-4 in the presence of Zn²âº.
Biochem J
; 454(2): 275-82, 2013 Sep 01.
Article
em En
| MEDLINE
| ID: mdl-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 Zn²âº. 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 Zn²âº. 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 Zn²âº 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 Zn²âº-mediated propofol inhibition. Overall, we discovered that propofol specifically and reversibly inhibits AQP4 through the interaction between Zn²âº and Cys²5³. The findings provide new insight into the functional regulation of AQP4 and may facilitate the identification of novel AQP4-specific inhibitors.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Zinco
/
Propofol
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Anestésicos Intravenosos
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Aquaporina 4
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Bicamadas Lipídicas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Biochem J
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Japão