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Vol. 57, Issue 5, 1021-1026, May 2000

Inhibition of Aquaporin-1 Water Permeability by Tetraethylammonium: Involvement of the Loop E Pore Region

Heddwen L. Brooks,1 John W. Regan, and Andrea J. Yool

Departments of Physiology (H.L.B., A.J.Y.) and Pharmacology (J.W.R., A.J.Y.), University of Arizona College of Medicine; and Department of Pharmacology and Toxicology, University of Arizona College of Pharmacy (J.W.R.), Tucson, Arizona

Previously, the only known blockers of water permeability through aquaporin-1 (AQP1) water channels were mercurial reagents such as HgCl2. For AQP1, inhibition by mercury has been attributed to the formation of a mercaptide bond with cysteine residue 189 found in the putative pore-forming region loop E. Here we show that the nonmercurial compound, tetraethylammonium (TEA) chloride, reduces the water permeability of human AQP1 channels expressed in Xenopus oocytes. After preincubation of the oocytes for 15 min with 100 µM TEA, AQP1 water permeability was reduced by 20 to 40%, a degree of partial block similar to that obtained with 15 min of incubation in 100 µM HgCl2. The reduction of water permeability was dose-dependent for tested concentrations up to 10 mM TEA. TEA blocks the Shaker potassium channel by interacting with a tyrosine residue in the outer pore region. We tested whether an analogous tyrosine residue in loop E of AQP1 could be involved in the binding of TEA. Using polymerase chain reaction, tyrosine 186 in AQP1, selected for its proximity to the mercury-binding site, was mutated to phenylalanine (Y186F), alanine (Y186A), or asparagine (Y186N). Oocyte expression of the mutant AQP1 channels showed that the water permeability of Y186F was equivalent to that of wild-type AQP1; the other mutant channels did not conduct water. However, in contrast to wild-type AQP1, the water permeability of Y186F was not reduced with 100 µM TEA. These results suggest that TEA reduces AQP1 water permeability by interacting with loop E.

1 Current address: Laboratory of Kidney and Electrolyte Metabolism, National Institutes of Health, Bldg. 10, Rm. 6N240, 10 Center Dr., MSC 1603, Bethesda, MD 20892-1603.

Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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