The Journal of General Physiology
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Published online 12 September 2005 doi:10.1085/jgp.200509334
The Rockefeller University Press, 0022-1295 $8.00
JGP, Volume 126, Number 4, 325-337
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ARTICLE

 Novel Insights Regarding the Operational Characteristics and Teleological Purpose of the Renal Na+-K+-Cl2 Cotransporter (NKCC2s) Splice Variants

Geneviève M. Brunet, Edith Gagnon, Charles F. Simard, Nikolas D. Daigle, Luc Caron, Micheline Noël, Marie-Hélène Lefoll, Marc J. Bergeron, and Paul Isenring

Nephrology Group, L'Hôtel-Dieu de Québec Research Center, Department of Medicine, Faculty of Medicine, Laval University, Québec, Canada G1R2J6

Correspondence to Paul Isenring: paul.isenring{at}crhdq.ulaval.ca

The absorptive Na+-K+-Cl– cotransporter (NKCC2) is a polytopic protein that forms homooligomeric complexes in the apical membrane of the thick ascending loop of Henle (TAL). It occurs in at least four splice variants (called B, A, F, and AF) that are identical to one another except for a short region in the membrane-associated domain. Although each of these variants exhibits unique functional properties and distributions along the TAL, their teleological purpose and structural organization remain poorly defined. In the current work, we provide additional insight in these regards by showing in mouse that the administration of either furosemide or an H2O-rich diet, which are predicted to alter NKCC2 expression in the TAL, exerts differential effects on mRNA levels for the variants, increasing those of A (furosemide) but decreasing those of F and AF (furosemide or H2O). Based on a yeast two-hybrid mapping analysis, we also show that the formation of homooligomeric complexes is mediated by two self-interacting domains in the COOH terminus (residues 671 to 816 and 910 to 1098), and that these complexes could probably include more than one type of variant. Taken together, the data reported here suggest that A, F, and AF each play unique roles that are adapted to specific physiological needs, and that the accomplishment of such roles is coordinated through the splicing machinery as well as complex NKCC2–NKCC2 interactions.

Abbreviations used in this paper: CCC, cation-Cl cotransporter; Ct, COOH terminus; ctl, control; EIR, essential interacting region; hu, human; ms, mouse; NKCC2, Na+-K+-Cl– cotransporter; OM, outer medulla; RT-PCR, reverse transcriptase PCR; sa, shark; TAL, thick ascending loop of Henle.


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