Cyclosporin A inhibits creatine uptake by altering surface expression of the creatine transporter.
The immunosuppressive drug cyclosporin A (CsA) inhibited the hCRT-1 cDNA-induced creatine uptake in Xenopus oocytes and the endogenous creatine uptake in cultured C(2)C(12) 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 K(m) and V(max) of creatine transport and also on the cell surface distribution of the creatine transporter. Although CsA treatment did not affect the K(m) (20-24 microm) for creatine, it significantly decreased the V(max) 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 approximately 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.
Tran
T T
TT
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA.
Dai
W
W
Sarkar
H K
HK
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D019921:Biotinylation; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003401:Creatine / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007700:Kinetics; D026901:Membrane Transport Proteins; D051379:Mice; D009132:Muscles / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000037:antagonists & inhibitors; D018075:RNA, Complementary / Q000378:metabolism; D013654:Taurine / Q000378:metabolism; D014981:Xenopus
D000906:Antibodies; D002352:Carrier Proteins; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins; D010446:Peptide Fragments; D018075:RNA, Complementary; C080679:creatine transporter; D013654:Taurine; D018698:Glutamic Acid; D016572:Cyclosporine; D003401:Creatine