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1 Center for Cell and Molecular Signaling and 2 Department of Physiology, Emory University School of Medicine, Atlanta, Georgia 30322; and 3 Renal Electrolyte Division, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213-2550
Rapamycin and FK-506 are immunosuppressive drugs that bind a ubiquitous immunophilin, FKBP12, but immunosuppressive mechanisms and side effects appear to be different. Rapamycin binds renal FKBP12 to change renal transport. We used cell-attached patch clamp to examine rapamycin's effect on Na+ channels in A6 cells. Channel NPo was 0.5 ± 0.08 (n = 6) during the first 5 min but fell close to zero after 20 min. Application of 1 µM rapamycin reactivated Na+ channels (NPo = 0.47 ± 0.1; n=6), but 1 µM FK-506 did not. Also, GF-109203X, a protein kinase C (PKC) inhibitor, mimicked the rapamycin-induced reactivation in a nonadditive manner. However, rapamycin did not reactivate Na+ channels if cells were exposed to 1 µM FK-506 before rapamycin. In PKC assays, rapamycin was as effective as the PKC inhibitor; however, epithelial Na+ channel (ENaC) phosphorylation was low under baseline conditions and was not altered by PKC inhibitors or activators. These results suggest that rapamycin activates Na+ channels by binding FKBP12 and inhibiting PKC, and, in renal cells, despite binding the same immunophilin, rapamycin and FK-506 activate different intracellular signaling pathways.
epithelial sodium channel; amiloride-sensitive sodium channels; protein kinase C; single channels
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