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J. Biol. Chem., Vol. 282, Issue 25, 18083-18093, June 22, 2007

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Homooligomeric and Heterooligomeric Associations between K⁺-Cl^– Cotransporter Isoforms and between K⁺-Cl^– and Na⁺-K⁺-Cl^– Cotransporters^*

From the Nephrology Research Group, L'Hôtel-Dieu de Québec Research Institution, Department of Medicine, Faculty of Medicine, Laval University, Québec, Québec G1R 2J6, Canada

Little is known regarding the quaternary structure of cation-Cl^– cotransporters (CCCs) except that the Na⁺-dependent CCCs can exist as homooligomeric units. Given that each of the CCCs exhibits unique functional properties and that several of these carriers coexist in various cell types, it would be of interest to determine whether the four K⁺-Cl^– cotransporter (KCC) isoforms and their splice variants can also assemble into such units and, more importantly, whether they can form heterooligomers by interacting with each other or with the secretory Na⁺-K⁺-Cl^– cotransporter (NKCC1). In the present work, we have addressed these questions by conducting two groups of analyses: 1) yeast two-hybrid and pull-down assays in which CCC-derived protein segments were used as both bait and prey and 2) coimmunoprecipitation and functional studies of intact CCCs coexpressed in Xenopus laevis oocytes. Through a combination of such analyses, we have found that KCC2 and KCC4 could adopt various oligomeric states (in the form of KCC2-KCC2, KCC4-KCC4, KCC2-KCC4, and even KCC4-NKCC1 complexes), that their carboxyl termini were probably involved in carrier assembly, and that the KCC4-NKCC1 oligomers, more specifically, could deploy unique functional features. Through additional coimmunoprecipitation studies, we have also found that KCC1 and KCC3 had the potential of assembling into various types of CCC-CCC oligomers as well, although the interactions uncovered were not characterized as extensively, and the protein segments involved were not identified in yeast two-hybrid assays. Taken together, these findings could change our views on how CCCs operate or are regulated in animal cells by suggesting, in particular, that cation-Cl^– cotransport achieves higher levels of functional diversity than foreseen.

Received for publication, August 15, 2006 , and in revised form, April 24, 2007.

^* This work was supported by grants from the Kidney Foundation of Canada and from the Canadian Institute of Health and Research (CIHR) through MOP-68949 and MOP-15405. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1 and Figs. S1 and S2.

¹ A CIHR Scholar.

² Holder of a CIHR Canadian Research Chair in Molecular Physiology and Professor of Medicine at Laval University. To whom correspondence should be addressed: L'Hôtel-Dieu de Québec Institution, 10 Rue McMahon, Québec, Québec G1R 2J6, Canada. Tel.: 418-691-5151 (ext. 15477); Fax: 418-692-5795; E-mail: paul.isenring{at}crhdq.ulaval.ca.

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