title: Phloretin differentially inhibits volume-sensitive and cyclic AMP-activated, but not Ca-activated, Cl(-) channels.
abstract: 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 Ca(2+)-activated Cl(-) channels using the whole-cell patch-clamp technique. Extracellular application of phloretin (over 10 microM) voltage-independently, and in a concentration-dependent manner (IC(50) approximately 30 microM), inhibited the Cl(-) current activated by a hypotonic challenge in human epithelial T84, Intestine 407 cells and mouse mammary C127/CFTR cells. In contrast, at 30 microM phloretin failed to inhibit cyclic AMP-activated Cl(-) currents in T84 and C127/CFTR cells. Higher concentrations (over 100 microM) of phloretin, however, partially inhibited the CFTR Cl(-) currents in a voltage-dependent manner. At 30 and 300 microM, phloretin showed no inhibitory effect on Ca(2+)-dependent Cl(-) currents induced by ionomycin in T84 cells. It is concluded that phloretin preferentially blocks volume-sensitive Cl(-) channels at low concentrations (below 100 microM) and also inhibits cyclic AMP-activated Cl(-) channels at higher concentrations, whereas phloretin does not inhibit Ca(2+)-activated Cl(-) channels in epithelial cells.
authors.affiliation: Department of Cell Physiology, National Institute for Physiological Sciences, Myodaiji-cho, Okazaki 444-8585, Japan.
authors.forename: H T
authors.initials: HT
authors.lastname: Fan
authors.forename: S
authors.initials: S
authors.lastname: Morishima
authors.forename: H
authors.initials: H
authors.lastname: Kida
authors.forename: Y
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D018118:Chloride Channels / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007038:Hypotonic Solutions / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007552:Isotonic Solutions / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010693:Phloretin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D018118:Chloride Channels; D007038:Hypotonic Solutions; D007476:Ionophores; D007552:Isotonic Solutions; D015759:Ionomycin; D000242:Cyclic AMP; D010693:Phloretin; D002118:Calcium