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-subunit
isoforms have a similar affinity for cardiac glycosides
Departments of 1 Physiology and Biophysics and 2 Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, Los Angeles, California 90089-9142
Three
-subunit isoforms of the sodium pump, which is the receptor for
cardiac glycosides, are expressed in human heart. The aim of this study
was to determine whether these isoforms have distinct affinities for
the cardiac glycoside ouabain. Equilibrium ouabain binding to membranes
from a panel of different human tissues and cell lines derived from
human tissues was compared by an F statistic to determine
whether a single population of binding sites or two populations of
sites with different affinities would better fit the data. For all
tissues, the single-site model fit the data as well as the two-site
model. The mean equilibrium dissociation constant
(Kd) for all samples calculated using the
single-site model was 18 ± 6 nM (mean ± SD). No difference
in Kd was found between nonfailing and failing
human heart samples, although the maximum number of binding sites in
failing heart was only ~50% of the number of sites in nonfailing
heart. Measurement of association rate constants and dissociation rate
constants confirmed that the binding affinities of the different human
-isoforms are similar to each other, although calculated
Kd values were lower than those determined by
equilibrium binding. These results indicate both that the affinity of
all human -subunit isoforms for ouabain is similar and that the
increased sensitivity of failing human heart to cardiac glycosides is
probably due to a reduction in the number of pumps in the heart rather
than to a selective inhibition of a subset of pumps with different
affinities for the drugs.
sodium pump; ouabain binding
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