Solute carrier family 12 member 2 (NKCC1)
Type: Family

The K+Cl- cotransporters (KCCs) constitute a branch of the electroneutral cation-coupled chloride cotransporter family SLC12 (Solute carrier family 12). The other branch of the SLC12 family is composed of the Na+-coupled chloride cotransporters, generally called N(K)CCs, that following the driving force imposed by the Na+:K+:ATPase translocate ions from the outside to the inside of the cell, thus having similar important roles as the KCCs in many physiological aspects, but in the opposite direction .

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.

Recent molecular studies have identified 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.

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 hypokalemia, metabolic alkalosis, salt-wasting and hypotension .

NKCC1 (SLC12A2, BSC2) was first cloned from the shark rectal gland, a model secretory epithelium . Subsequently, mammalian homologues were cloned from mouse and human tissues. NKCC1 has a wide distribution and is a basolateral secretory isoform, that plays fundamental roles in regulating trans-epithelial ion movement, cell volume, chloride homeostasis and neuronal excitability in a diverse range of tissues . Its broad distribution also suggests that it may be involved in cell volume regulation and ionic homeostasis . The human isoform consists of 1212 amino acid residues and shares ~90 identity with the mouse homologue. It shows lower identity to other members of the cation-chloride co-transporter superfamily, being ~40% identical to the thiazide-sensitive Na-Cl co-transporter.