FK506 inhibits Cl- secretion in airway epithelium via calcineurin-independent mechanism

FK506 (tacrolimus)-binding protein (FKBP) is associated with intracellular Ca2+ release channel;md 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 (I-SC), in cultured bovine tracheal epithelial cells . Addition of ATP induced an increase in [Ca2+](i), and this response was d ose dependently inhibited by FK506. Rapamycin, which binds FKBP with high a ffinity, likewise inhibited the [Ca2+](i) rise, but cyclosporin A, a specif ic calcineurin inhibitor, did not. In Cl- secretion studies using Ussing ch amber, ATP increased Ca2+-mediated I-SC in amiloride-treated cells, an effe ct that was inhibited by FK506 and rapamycin but not by cyclosporin A. Ther efore, FK506 inhibits Ca2+ mobilization in airway epithelium via FKBP but n ot calcineurin-dependent mechanism, which may result in the suppression of Ca2+ activated Cl- secretion. (C) 2001 Elsevier Science B.V. All rights res erved.