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cotransport by mercury
1 Yale University School of Medicine, New Haven, Connecticut 06510; and 2 Nephrology Group, Department of Medicine, Faculty of Medicine, Research Center L'Hôtel-Dieu de Québec, Laval University, Québec, Canada G1R 2J6
Mercury alters the
function of proteins by reacting with cysteinyl sulfhydryl
(SH
) groups. The
inorganic form (Hg2+) is toxic
to epithelial tissues and interacts with various transport proteins
including the Na+ pump and
Cl channels. In this study,
we determined whether the
Na+-K+-Cl
cotransporter type 1 (NKCC1), a major ion pathway in secretory tissues,
is also affected by mercurial substrates. To characterize the
interaction, we measured the effect of
Hg2+ on ion transport by the
secretory shark and human cotransporters expressed in HEK-293 cells.
Our studies show that Hg2+
inhibits
Na+-K+-Cl
cotransport, with inhibitor constant
(Ki) values of
25 µM for the shark carrier (sNKCC1) and 43 µM for the
human carrier. In further studies, we took advantage of species
differences in Hg2+ affinity to
identify residues involved in the interaction. An analysis of
human-shark chimeras and of an sNKCC1 mutant
(Cys-697
Leu) reveals that transmembrane domain 11 plays an essential role in Hg2+
binding. We also show that modification of additional
SH groups by thiol-reacting
compounds brings about inhibition and that the binding sites are not
exposed on the extracellular face of the membrane.
cation-chloride carriers; mutagenesis; binding sites
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