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Originally published In Press as doi:10.1074/jbc.C200021200 on January 28, 2002

J. Biol. Chem., Vol. 277, Issue 11, 8767-8770, March 15, 2002
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ACCELERATED PUBLICATION
Spatially Distributed Alternative Splice Variants of the Renal Na-K-Cl Cotransporter Exhibit Dramatically Different Affinities for the Transported Ions*

Ignacio GiménezDagger , Paul Isenring§, and Biff Forbush

From the Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06511

Three splice variants of the renal Na-K-Cl cotransporter (NKCC2 F, A, and B) are spatially distributed along the thick ascending limb of the mammalian kidney. To test whether NKCC2 splice variants differ in ion transport characteristics we expressed cDNAs encoding rabbit NKCC2 F, A, and B in Xenopus oocytes and determined the ion dependence of bumetanide-sensitive 86Rb influx. The three splice variants of NKCC2 showed dramatic differences in their kinetic behavior. The medullary variant F exhibited 3-4-fold lower affinity than variants A and B for Na+ and K+. Chloride affinities also markedly distinguish the three variants (KmF = 111.3, KmA = 44.7, and KmB = 8.9 mM Cl-). Thus, the kinetic properties of the NKCC2 splice variants are consistent with the spatial distribution of the variants along the thick ascending limb as they are involved in reabsorbing Na+, K+, and Cl- from a progressively diluted fluid in the tubule lumen. Variant B also showed an anomalous inhibition of rubidium influx at high extracellular Na+ concentrations, possibly important in its highly specialized role in the macula densa. The adaptation of the kinetic characteristics of the NKCC2 variants to the luminal concentrations of substrate represents an excellent example of functional specialization and diversity that can be achieved through alternative mRNA splicing.

* This research was supported by National Institutes of Health Grant DK-17433 and a fellowship (to I. G.) from the Ministerio de Educación y Cultura of Spain.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06520-8026. Tel.: 203-7373-2586; Fax: 203-785-6834; E-mail: ignacio.gimenez@yale.edu.

§ Present address: Groupe de Recherche en Nephrologie, Dept. of Medicine, Faculty of Medicine, Laval University, Quebec G1R 2J6, Canada.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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