FK506 inhibits Cl- secretion in airway epithelium via calcineurin-independent mechanism.
FK506 (tacrolimus)-binding protein (FKBP) is associated with intracellular Ca2+ release channel and modulates its function. To elucidate the effect of FK506 on Ca2+ dynamics and Ca2+-mediated Cl- secretion in airway epithelium, we studied intracellular Ca2+ ([Ca2+]i) concentration and Cl(-)-dependent short-circuit current (Isc), in cultured bovine tracheal epithelial cells. Addition of ATP induced an increase in [Ca2+]i, and this response was dose dependently inhibited by FK506. Rapamycin, which binds FKBP with high affinity, likewise inhibited the [Ca2+]i rise, but cyclosporin A, a specific calcineurin inhibitor, did not. In Cl- secretion studies using Ussing chamber, ATP increased Ca2+-mediated Isc in amiloride-treated cells, an effect that was inhibited by FK506 and rapamycin but not by cyclosporin A. Therefore, FK506 inhibits Ca2+ mobilization in airway epithelium via FKBP but not calcineurin-dependent mechanism, which may result in the suppression of Ca2+-activated Cl- secretion.
Kanoh
S
S
Third Department of Medicine, National Defense Medical College, Saitama, Japan.
Kondo
M
M
Tamaoki
J
J
Kobayashi
H
H
Motoyoshi
K
K
Nagai
A
A
D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D004347:Drug Interactions; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*; D022021:Tacrolimus Binding Proteins / Q000494:pharmacology*; D014132:Trachea
D002712:Chlorides; D007166:Immunosuppressive Agents; D000255:Adenosine Triphosphate; D019703:Calcineurin; D022021:Tacrolimus Binding Proteins; D002118:Calcium; D016559:Tacrolimus