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J. Biol. Chem., Vol. 275, Issue 39, 30326-30334, September 29, 2000
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From the The K+-Cl
Functional Comparison of the K+-Cl
Cotransporters KCC1 and KCC4*
§,,
Molecular Physiology Unit, Instituto
Nacional de Ciencias Médicas y Nutrición Salvador
Zubirán and Instituto de Investigaciones Biomédicas,
Universidad Nacional Autónoma de México, Tlalpan 14000, Mexico City, Mexico and the ¶ Division of Nephrology and
Hypertension, Department of Medicine, Vanderbilt University Medical
Center, Nashville, Tennessee 37232
cotransporters (KCCs) are members of the cation-chloride cotransporter
gene family and fall into two phylogenetic subgroups: KCC2 paired with
KCC4 and KCC1 paired with KCC3. We report a functional comparison in
Xenopus oocytes of KCC1 and KCC4, widely expressed
representatives of these two subgroups. KCC1 and KCC4 exhibit
differential sensitivity to transport inhibitors, such that KCC4 is
much less sensitive to bumetanide and furosemide. The efficacy of these
anion inhibitors is critically dependent on the concentration of
extracellular K+, with much higher inhibition in 50 mM K+ versus 2 mM
K+. KCC4 is also uniquely sensitive to 10 mM
barium and to 2 mM trichlormethiazide. Kinetic
characterization reveals divergent affinities for K+
(Km values of ~25.5 and 17.5 mM for
KCC1 and KCC4, respectively), probably due to variation within the
second transmembrane segment. Although the two isoforms have equivalent
affinities for Cl, they differ in the anion selectivity
of K+ transport (Cl > SCN = Br > PO43 > I
for KCC1 and Cl > Br > PO43 = I > SCN
for KCC4). Both KCCs express minimal K+-Cl
cotransport under isotonic conditions, with significant activation by
cell swelling under hypotonic conditions. The cysteine-alkylating agent
N-ethylmaleimide activates
K+-Cl cotransport in isotonic
conditions but abrogates hypotonic activation, an unexpected
dissociation of N-ethylmaleimide sensitivity and volume
sensitivity. Although KCC4 is consistently more volume-sensitive, the
hypotonic activation of both isoforms is critically dependent on
protein phosphatase 1. Overall, the functional comparison of these
cloned K+-Cl cotransporters reveals important
functional, pharmacological, and kinetic differences with both
physiological and mechanistic implications.
*
This work was supported by Consejo Nacional de Ciencia y
Tecnologia Grant 97629m and Howard Hughes Medical Institute Grant 75197-553601 (to G. G.) and National Institutes of Health Grants K11
DK02328 and RO1 DK57708 (to D. B. M.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
International Scholar of the Howard Hughes Medical
Institute. To whom correspondence should be addressed: Molecular
Physiology Unit, Vasco de Quiroga No. 15, Tlalpan 14000, México
City, Mexico. Tel.: 525-513-3868; Fax: 525-655-0382; E-mail:
gamba@mailer.main.conacyt.mx.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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