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Physiological Reviews, Vol. 80, No. 1, January 2000, pp. 211-276
Copyright ©2000 by the American Physiological Society
Department of Biology, Biological Research Laboratories, Syracuse, New York
Russell, John M.
Sodium-Potassium-Chloride Cotransport. Physiol. Rev. 80: 211-276, 2000.
Obligatory, coupled
cotransport of Na+, K+, and Cl
by
cell membranes has been reported in nearly every animal cell type. This review examines the current status of our knowledge about this ion
transport mechanism. Two isoforms of the
Na+-K+-Cl cotransporter (NKCC)
protein (~120-130 kDa, unglycosylated) are currently known. One
isoform (NKCC2) has at least three alternatively spliced variants and
is found exclusively in the kidney. The other (NKCC1) is found in
nearly all cell types. The NKCC maintains intracellular
Cl concentration ([Cl]i) at
levels above the predicted electrochemical equilibrium. The high
[Cl]i is used by epithelial tissues to
promote net salt transport and by neural cells to set synaptic
potentials; its function in other cells is unknown. There is
substantial evidence in some cells that the NKCC functions to offset
osmotically induced cell shrinkage by mediating the net influx of
osmotically active ions. Whether it serves to maintain cell volume
under euvolemic conditons is less clear. The NKCC may play an important
role in the cell cycle. Evidence that each cotransport cycle of the
NKCC is electrically silent is discussed along with evidence for the
electrically neutral stoichiometries of 1 Na+:1
K+:2 Cl
(for most cells) and 2 Na+:1
K+:3 Cl (in squid axon). Evidence that the
absolute dependence on ATP of the NKCC is the result of regulatory
phosphorylation/dephosphorylation mechanisms is decribed.
Interestingly, the presumed protein kinase(s) responsible has not been
identified. An unusual form of NKCC regulation is by
[Cl]i. [Cl]i in
the physiological range and above strongly inhibits the NKCC. This
effect may be mediated by a decrease of protein phosphorylation. Although the NKCC has been studied for ~20 years, we are only beginning to frame the broad outlines of the structure, function, and
regulation of this ubiquitous ion transport mechanism.
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