| Literature References | 1. PAYNE, J.A. AND FORBUSH, B., III.
Molecular characterization of the epithelial Na-K-Cl cotransporter
isoforms.
CURR.OPIN.CELL BIOL. 7 493-503 (1995).
2. SIMON, D.B. AND LIFTON, R.P.
Mutations in Na(K)Cl transporters in Gitelman's and Bartter's syndromes.
CURR.OPIN.CELL BIOL. 10 450-454 (1998).
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| Documentation | 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 trans-
epithelial 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
[1]. 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 (PR01081) 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 hypokalaemia, metabolic alkalosis, salt-
wasting and hypotension [2].
NAKCLTRNSPRT is a 3-element fingerprint that provides a signature for
Na-K-Cl co-transporters. The fingerprint was derived from an initial
alignment of 6 sequences: the motifs were drawn from conserved regions
within the N-terminal ~2/3 of the alignment - motif 1 resides within the
putative cytoplasmic N-terminus; and motifs 2 and 3 lie within the fourth
and fifth presumed extracellular domains, respectively. Two iterations on
SPTR37_9f were required to reach convergence, at which point a true set
comprising 10 sequences was identified.
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