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J. Biol. Chem., Vol. 275, Issue 46, 35708-35714, November 17, 2000
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From the Department of Molecular Physiology and Biophysics, Baylor
College of Medicine, Houston, Texas 77030
The immunosuppressive drug cyclosporin A (CsA)
inhibited the hCRT-1 cDNA-induced creatine uptake in
Xenopus oocytes and the endogenous creatine uptake in
cultured C2C12 muscle cells in a dose- and
time-dependent manner. FK506, another potent
immunosuppressant, was unable to mimic the effect of CsA suggesting
that the inhibitory effect of CsA was specific. To delineate the
mechanism underlying, we investigated the effect of CsA on the
Km and Vmax of creatine
transport and also on the cell surface distribution of the creatine
transporter. Although CsA treatment did not affect the
Km (20-24 µM) for creatine, it
significantly decreased the Vmax of creatine
uptake in both oocytes and muscle cells. CsA treatment reduced the cell
surface expression level of the creatine transporter in the muscle
cells by ~60% without significantly altering its total expression
level, and the reduction in the cell surface expression paralleled the
decrease in creatine uptake. Taken together, our results suggest that
CsA inhibited creatine uptake by altering the surface abundance of the
creatine transporter. We propose that CsA impairs the targeting of the
creatine transporter by inhibiting the function of an associated
cyclophilin, resulting in an apparent loss in surface expression of the
creatine transporter. Our results also suggest that prolonged exposure
to CsA may result in chronically creatine-depleted muscle, which may be
a cause for the development of CsA-associated clinical myopathies in
organ transplant patients.
Cyclosporin A Inhibits Creatine Uptake by Altering Surface
Expression of the Creatine Transporter*
*
This work was supported in part by American Heart
Association Grant-in-Aid 95012190 and the USDA/Agricultural Research
Service under Cooperative Agreement Grant 58-6255-6001.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.
To whom correspondence should be addressed: Dept. of Molecular
Physiology and Biophysics, Baylor College of Medicine, One Baylor
Plaza, Houston, TX 77030. Tel.: 713-798-4700; Fax: 713-798-3475; E-mail: hsarkar@bcm.tmc.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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