The immunosuppressant cyclosporin A (CsA) reduced the functional expression of Kir2.1 potassium channels in Xenopus oocytes in a dose-dependent manner with an IC50 of 11 microM when the oocytes were incubated with CsA after RNA injection. FK506 was less effective than CsA; cyclosporin H, a non-immunosuppressive derivative of CsA, did not have a significant effect. CsA did not impair protein synthesis since other potassium channel types (Kir1.1, Kv1.1, Kv1.4) were much less sensitive to CsA. Our results suggest that the functional expression of Kir2.1 channels is facilitated by the peptidyl-prolyl isomerase cyclophilin. The observations illustrate a new role of CsA in regulation of membrane ion transport, and may provide an alternative explanation for CsA-induced side effects in clinical use.