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

Abstract

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 and 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 and Ca2--activated Cl- channels using the whole-cell patch-clamp technique. 2. Extracellular application of phloretin (over 10 μM) voltage-independently, and in a concentration-dependent manner (IC50 ∼ 30 μM), 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 μM phloretin failed to inhibit cyclic AMP-activated Cl- currents in T84 and C127/CFTR cells. Higher concentrations (over 100 μM) of phloretin, however, partially inhibited the CFTR Cl- currents in a voltage-dependent manner. 4. At 30 and 300 μM, phloretin showed no inhibitory effect on Ca2+-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 μM) and also inhibits cyclic AMP-activated Cl- channels at higher concentrations, whereas phloretin does not inhibit Ca2+-activated Cl- channels in epithelial cells.