Cyclosporin A inhibits creatine uptake by altering surface expression of the creatine transporter

The immunosuppressive drug cyclosporin A (CsA) inhibited the hCRT-1 cDNA-in duced 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 s uggesting 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-ma x of creatine transport and also on the cell surface distribution of the cr eatine transporter, Although CsA treatment did not affect the K-m (20-24 mu M) for creatine, it significantly decreased the V-max of creatine uptake in both oocytes and muscle cells. CsA treatment reduced the cell surface expr ession level of the creatine transporter in the muscle cells by similar to 60% without significantly altering its total expression level, and the redu ction in the cell surface expression paralleled the decrease in creatine up take, Taken together, our results suggest that CsA inhibited creatine uptak e by altering the surface abundance of the creatine transporter. We propose that CsA impairs the targeting of the creatine transporter by inhibiting t he function of an associated cyclophilin, resulting in an apparent loss in surface expression of the creatine transporter. Our results also suggest th at prolonged exposure to CsA may result in chronically creatine-depleted mu scle, which may be a cause for the development of CsA-associated clinical m yopathies in organ transplant patients.