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 known blocker of glucose uniport Ind anion antiport, have not been examined. In the present study. we investigated the effects of phloretin on volume-sensitive Cl(-) channels in comparison with cyclic AMP-activated CFTR Cl(-) channels Ind Ca(2+)-activated Cl(-) channels using the whole-cell patch-clamp technique. 2 Extracellular application of phloretin (over 10 muM) voltage-independently, and in a concentration-dependent manner (IC(50) similar to 30 muM), inhibited 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 Cl(-) currents in T84 and C127/CFTR cells. Higher concentrations (over 100 mum) of phloretin, however, partially inhibited the CFTR Cl(-) currents in a voltage-dependent manner, 4 At 30 and 300 mum, phloretin showed no inhibitory effect on Ca(2+)-dependent 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 AMP-activated Cl(-) channels at higher concentrations, whereas phloretin does not inhibit Ca(2+)-activated Cl(-) channels in epithelial cells.