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1 Division of Biomedical Sciences, University of California, Riverside, California 92521; and 2 Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
Na-K-2Cl cotransporter (NKCC)
and K-Cl cotransporter (KCC) play key roles in cell volume
regulation and epithelial Cl
transport. Reductions in
either cell volume or cytosolic Cl concentration
([Cl]i) stimulate a corrective uptake of
KCl and water via NKCC, whereas cell swelling triggers KCl loss via
KCC. The dependence of these transporters on volume and
[Cl]i was evaluated in model duck red blood
cells. Replacement of [Cl]i with
methanesulfonate elevated the volume set point at which NKCC activates
and KCC inactivates. The set point was insensitive to cytosolic ionic
strength. Reducing [Cl]i at a constant
driving force for inward NKCC and outward KCC caused the cells to adopt
the new set point volume. Phosphopeptide maps of NKCC indicated that
activation by cell shrinkage or low [Cl]i
is associated with phosphorylation of a similar constellation of
Ser/Thr sites. Like shrinkage, reduction of
[Cl]i accelerated NKCC phosphorylation
after abrupt inhibition of the deactivating phosphatase with
calyculin A in vivo, whereas [Cl] had no specific
effect on dephosphorylation in vitro. Our results indicate that NKCC
and KCC are reciprocally regulated by a negative feedback system dually
modulated by cell volume and [Cl]. The major effect of
Cl on NKCC is exerted through the volume-sensitive kinase
that phosphorylates the transport protein.
sodium-potassium-chloride cotransport; intracellular chloride; cell volume regulation; ionic strength; cell water content; sodium-potassium-chloride cotransporter phosphorylation
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