Molecular characteristics and physiological roles of Na+ -K+ -Cl- cotransporter 2.

Andree‐Anne Marcoux,Marie‐Jeanne Fiola,Samira Slimani,Paul Isenring,Fabrice Mac‐Way,Alexandre P Garneau,Laurence E Tremblay

doi:10.1002/jcp.29997

Andree‐Anne Marcoux, Marie‐Jeanne Fiola + Show 5 more

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https://doi.org/10.1002/jcp.29997

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Abstract

Na+–K+–Cl− cotransporter 2 (NKCC2; SLC12A1) is an integral membrane protein that comes as three splice variants and mediates the cotranslocation of Na+, K+, and Cl− ions through the apical membrane of the thick ascending loop of Henle (TALH). In doing so, and through the involvement of other ion transport systems, it allows this nephron segment to reclaim a large fraction of the ultrafiltered Na+, Cl−, Ca2+, Mg2 +, and HCO3 − loads. The functional relevance of NKCC2 in human is illustrated by the many abnormalities that result from the inactivation of this transport system through the use of loop diuretics or in the setting of inherited disorders. The following presentation aims at discussing the physiological roles and molecular characteristics of Na+–K+–Cl− cotransport in the TALH and those of the individual NKCC2 splice variants more specifically. Many of the historical and recent data that have emerged from the experiments conducted will be outlined and their larger meaning will also be placed into perspective with the aid of various hypotheses.

Highlights

Residues involved in ion transport Given that the main splice variants are identical to each other except for the residue sequence of the TMD2–CL1 domain, their individual functional characteristics have to be explained by the variable composition of exon 4
We have seen that Na+–K+–Cl− cotransporter 2 (NKCC2) is of crucial importance to the normal operation of the thick ascending loop of Henle (TALH) as it contributes to extracellular fluid volume maintenance, urinary concentration/dilution, tubuloglomerular feedback (TGF), Mg2+ homeostasis, and acid‐base balance
While the probes and inhibitors required could consist of pharmacologic agents or small peptides, prey sites would probably have to be included in the TMD2–CL1 domains

Summary

| INTRODUCTION

Na+–K+–Cl− cotransporter 2 (NKCC2; SLC12A1) is a cation‐Cl− coof extrarenal tissues as well but at lower levels. NKCC2 was linked to an antenatal thick ascending loop of Henle (TALH) in the mammalian kidney form of salt‐losing nephropathy called classical Bartter syndrome and (Kaplan et al, 1996; Nielsen, Maunsbach, Ecelbarger, & Knepper, to blood pressure (BP) variations in the population (Acuna et al, 2011; 1998). Because of this transport mechanism, NKCC2‐expressing cells Simon et al, 1996; Starremans, Kersten, Knoers, van den Heuvel, &. A recent publication on the high‐resolution structure of NKCC1 should become quite helpful to this end

| MAIN TEXT

Findings

| CONCLUSION AND PERSPECTIVES