Solute carrier family 12 member 1 (Slc12a1)
Type: Family

Solute carrier family 12 member 1 (SLC12A1 or NKCC2) is an apical absorptive Na-K-Cl co-transporter isoform. In contrast to the wide tissue distribution of NKCC1, expression of the NKCC2 isoform is restricted to the vertebrate kidney, where it is involved in urinary concentration . Subsequent studies revealed that three variants exist, differing by 31 amino acids, which are generated by alternatively splicing. They show differential distributions within the kidney, suggesting they may subserve varying functions . Mutations in the gene encoding the renal-specific isoform of the Na-K-Cl co-transporter (NKCC2) give rise to Bartter's Syndrome Type 1, an inherited kidney disease characterised by hypokalaemia, metabolic alkalosis, salt-wasting and hypotension .

The Na-K-Cl co-transporters are a family of integral membrane proteins that are ubiquitously expressed in animal tissues, serving a variety of functions. In cells of Cl
-
absorptive and Cl
-
secretory epithelia, Na-K-Cl co-transport serves as the major Cl
-
entry pathway, and functions in concert with other membrane ion channels and pumps to carry out net transepithelial movement of salt. This vectorial transport of Cl
-
across epithelia is involved in the reabsorption of salt in the vertebrate kidney (which is crucial for urinary concentration), and in the secretion of salt in such tissues as the mammalian intestine and trachea. In addition, Na-K-Cl co-transport is known to play a role in cell volume regulation in most mammalian cell types. The proteins mediate the coupled, electroneutral transport of sodium, potassium and chloride ions across the plasma membrane of cells (with a stoichiometry of 1:1:2, respectively). Co-transport of all three ions is obligatory, since absence of one is sufficient to prevent ion movement. Their transport activity does not alter the cell's membrane potential, thus the driving force for the transport is determined solely by the chemical gradients of the three transported ions; hence, under normal physiological conditions, the direction will be inward.

There are two distinct isoforms: one from Cl
-
secretory epithelia, NKCC1; and another, NKCC2, found specifically in the diluting segment of the vertebrate kidney, a Cl
-
absorptive epithelium . They show lowish amino acid sequence identity (~58%); nevertheless, they have rather similar hydropathy profiles, with hydrophilic N- and C-termini, flanking a central hydrophobic domain. Their N-termini show considerable variation, unlike the central domain (containing the 12 putative transmembrane (TM) domains) and their C-termini, which are well conserved (~70%). Both isoforms are known to be glycosylated and, consistent with this, consensus sites for N-linked glycosylation are located within the large hydrophilic loop between presumed TM domains 7 and 8. Sequence comparisons with other cloned ion co-transporters reveals that Na-K-Cl co-transporters belong to a superfamily of electroneutral cation-chloride co-transporters, which includes the K-Cl co-transporter (

) and the thiazide-sensitive Na-Cl co-transporter. All share a similar predicted membrane topology of 12 TM regions in a central hydrophobic domain, together with hydrophilic N- and C-termini that are likely cytoplasmic.