Inhibition of cystic fibrosis transmembrane conductance regulator chloride channel currents by arachidonic acid.
Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is inhibited by a number of different classes of organic anions which are able to enter and block the channel pore from its cytoplasmic end. Here I show, using patch clamp recording from CFTR-transfected baby hamster kidney cell lines, that the cis-unsaturated fatty acid arachidonic acid also inhibits CFTR Cl- currents when applied to the cytoplasmic face of excised membrane patches. This inhibition was of a relatively high affinity compared with other known CFTR inhibitors, with an apparent Kd of 6.5 +/- 0.9 microM. However, in contrast with known CFTR pore blockers, inhibition by arachidonic acid was only very weakly voltage dependent, and was insensitive to the extracellular Cl- concentration. Arachidonic acid-mediated inhibition of CFTR Cl- currents was not abrogated by inhibitors of lipoxygenases, cyclooxygenases or cytochrome P450, suggesting that arachidonic acid itself, rather than some metabolite, directly affects CFTR. Similar inhibition of CFTR Cl- currents was seen with other fatty acids, with the rank order of potency linoleic > or = arachidonic > or = oleic > elaidic > or = palmitic > or = myristic. These results identify fatty acids as novel high affinity modulators of the CFTR Cl- channel.
Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada. paul.linsdell@dal.ca
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D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology*; D002460:Cell Line; D003022:Clotrimazole / Q000494:pharmacology; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000502:physiology; D005227:Fatty Acids / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D009637:Masoprocol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology
D016861:Cyclooxygenase Inhibitors; D005227:Fatty Acids; D006131:Growth Inhibitors; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016718:Arachidonic Acid; D009637:Masoprocol; D003022:Clotrimazole; D007213:Indomethacin