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J. Biol. Chem., Vol. 276, Issue 34, 31535-31541, August 24, 2001
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From the Department of Biochemistry and Medicine, McGill
University, Montreal, Quebec H3G 1A4, Canada
Previous studies showed that the
Mechanistic Basis for Kinetic Differences between the
Rat
1, 2, and 3 Isoforms of the Na,K-ATPase*
1, 2, and
3 isoforms of the catalytic subunit of the Na,K-ATPase differ in
their apparent affinities for the ligands ATP, Na+,
and K+. For the rat isoforms transfected into HeLa cells,
K'ATP for ATP binding at its low affinity site
is lower for 2 and 3 compared with 1; relative to 1 and
2, 3 has a higher K'Na and lower K'K (Jewell, E. A., and Lingrel,
J. B (1991) J. Biol. Chem. 266, 16925-16930;
Munzer, J. S., Daly, S. E., Jewell-Motz, E. A., Lingrel, J. B, and Blostein, R. (1994) J. Biol.
Chem. 269, 16668-16676). The experiments described in the
present study provide insight into the mechanistic basis for these
differences. The results show that 2 differs from 1 primarily by
a shift in the E1 
E2 equilibrium in favor of
E1 form(s) as evidenced by (i) a ~20-fold increase in IC50 for vanadate, (ii) decreased catalytic
turnover, and (iii) notable stability of Na,K-ATPase activity at acidic pH. In contrast, despite its lower K'ATP
compared with 1, the E1 E2 poise of 3 is not shifted toward
E1. Distinct intrinsic interactions with
Na+ ions are underscored by the marked selectivity for
Na+ over Li+ of 3 compared with either 1
or 2 and higher K'Na for cytoplasmic Na+, which persists over a 100-fold range in proton
concentration, independent of the presence of K+. The
kinetic analysis also suggests 3-specific differences in relative
rates of partial reactions, which impact this isoform's distinct
apparent affinities for both Na+ and K+.
*
This work was supported by grants from the Medical Research
Council of Canada and Quebec Heart and Stroke Foundation (to R. B.).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.
Supported by a predoctoral traineeship from the Heart and Stroke
Foundation of Canada.
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