Nickel and Extracellular Acidification Inhibit the Water Permeability of Human Aquaporin-3 in Lung Epithelial Cells

• Published in: The Journal of biological chemistry 2003-08, Vol.278 (32), p.30037-30043
• Main Authors: Zelenina, Marina, Bondar, Alexander A., Zelenin, Sergey, Aperia, Anita
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Aquaporin 3; Aquaporin 4; Aquaporin 5; Aquaporins - chemistry; Aquaporins - metabolism; Binding Sites; Cadmium - chemistry; Cell Line; DNA, Complementary - metabolism; Dose-Response Relationship, Drug; Epithelial Cells - metabolism; Histidine - chemistry; Humans; Hydrogen-Ion Concentration; Lung - cytology; Membrane Proteins; Molecular Sequence Data; Mutation; Nickel - chemistry; Nickel - pharmacology; Point Mutation; Protein Structure, Tertiary; Serine - chemistry; Transfection; Tryptophan - chemistry; Water - chemistry; Zinc - chemistry
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M302206200

Nickel is a common cause of pneumoconiosis. Here, we show that nickel inactivates aquaporin (AQP)-3, the water channel expressed apically in epithelial cells of human terminal airways. Human AQP3 was transiently transfected into human lung cells, and water permeability was measured in transfected and neighboring untransfected cells. Incubation with NiCl2 rapidly, dose-dependently, and reversibly decreased water permeability in AQP3-expressing cells. Acidification of the extracellular medium also caused rapid, dose-dependent, and reversible inhibition of AQP3. Sensitivity of AQP3 to nickel was lower at alkaline pH than at neutral and acidic pH. Cells transfected with human AQP4 and AQP5, which are also expressed in airway epithelia, were insensitive to nickel and extracellular acidification. Zinc and cadmium, other common causes of pneumoconiosis, had no effect on the water permeability of AQP3. Three extracellular residues, Trp128, Ser152, and His241, were responsible for the blocking effect of nickel on human AQP3. Ser152 was identified as a common site for nickel and pH sensitivity. His53, Tyr124, and His154 were also involved in regulation of AQP3 by extracellular pH. In addition, the aromatic side chain of His154 was shown to be important for the water permeability of AQP3. Our results imply that nickel and extracellular pH may modulate lung water clearance and that defective water clearance may be an early component of nickel-induced lung disease.