Phloretin differentially inhibits volume-sensitive and cyclic AMP-activated, but not Ca-activated, Cl- channels

1 Some phenol derivatives are known to block volume-sensitive Cl- channels. However, effects on the channel of the bisphenol phloretin, which is a kno wn blocker of glucose uniport Ind anion antiport, have not been examined. I n the present study. we investigated the effects of phloretin on volume-sen sitive Cl- channels in comparison with cyclic AMP-activated CFTR Cl- channe ls Ind Ca2+-activated Cl- channels using the whole-cell patch-clamp techniq ue. 2 Extracellular application of phloretin (over 10 muM) voltage-independentl y, and in a concentration-dependent manner (IC50 similar to 30 muM), inhibi ted the Cl- current activated by a hypotonic challenge in human epithelial T84, Intestine 407 cells and mouse mammary C127/CFTR cells. 3 In contrast, at 30 muM phloretin failed to inhibit cyclic AMP-activated C l- currents in T84 and C127/CFTR cells. Higher concentrations (over 100 mum ) of phloretin, however, partially inhibited the CFTR Cl- currents in a vol tage-dependent manner, 4 At 30 and 300 mum, phloretin showed no inhibitory effect on Ca2+-dependen t Cl- currents induced by ionomycin in T84 cells. 5 It is concluded that phloretin preferentially blocks volume-sensitive Cl- channels at low concentrations (below 100 mum) and also inhibits cyclic AM P-activated Cl- channels at higher concentrations, whereas phloretin does n ot inhibit Ca2+-activated Cl- channels in epithelial cells.