| Description: |
Solute carrier family 12 member 1 (SLC12A1 or NKCC2) is an apical absorptive Na-K-Cl co-transporterisoform. In contrast to the wide tissue distribution of NKCC1, expressionof the NKCC2 isoform is restricted to the vertebrate kidney, where it isinvolved in urinary concentration []. Subsequent studies revealed thatthree variants exist, differing by 31 amino acids, which are generatedby alternatively splicing. They show differential distributions withinthe kidney, suggesting they may subserve varying functions []. Mutations in the gene encoding the renal-specific isoform of the Na-K-Clco-transporter (NKCC2) give rise to Bartter's Syndrome Type 1, an inheritedkidney disease characterised by hypokalaemia, metabolic alkalosis,salt-wasting and hypotension [].The Na-K-Cl co-transporters are a family of integral membrane proteins thatare ubiquitously expressed in animal tissues, serving a variety offunctions. In cells of Cl-absorptive and Cl-secretory epithelia, Na-K-Clco-transport serves as the major Cl-entry pathway, and functions inconcert with other membrane ion channels and pumps to carry out nettransepithelial movement of salt. This vectorial transport of Cl-acrossepithelia is involved in the reabsorption of salt in the vertebrate kidney(which is crucial for urinary concentration), and in the secretion of saltin 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 inmost mammalian cell types. The proteins mediate the coupled, electroneutraltransport of sodium, potassium and chloride ions across the plasma membraneof cells (with a stoichiometry of 1:1:2, respectively). Co-transport of allthree ions is obligatory, since absence of one is sufficient to prevent ionmovement. Their transport activity does not alter the cell's membranepotential, thus the driving force for the transport is determined solelyby the chemical gradients of the three transported ions; hence, undernormal physiological conditions, the direction will be inward.There are two distinct isoforms: one fromCl-secretory epithelia, NKCC1; and another, NKCC2, found specifically inthe 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- andC-termini, flanking a central hydrophobic domain. Their N-termini showconsiderable variation, unlike the central domain (containing the 12putative transmembrane (TM) domains) and their C-termini, which are wellconserved (~70%). Both isoforms are known to be glycosylated and, consistentwith this, consensus sites for N-linked glycosylation are located within thelarge hydrophilic loop between presumed TM domains 7 and 8. Sequencecomparisons with other cloned ion co-transporters reveals that Na-K-Clco-transporters belong to a superfamily of electroneutral cation-chlorideco-transporters, which includes the K-Cl co-transporter () and thethiazide-sensitive Na-Cl co-transporter. All share a similar predictedmembrane topology of 12 TM regions in a central hydrophobic domain,together with hydrophilic N- and C-termini that are likely cytoplasmic. |
