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 K(d) of 6.5 ± 0.9 μM. 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 ≥ arachidonic ≥ oleic > elaidic ≥ palmitic ≥ myristic. These results identify fatty acids as novel high affinity modulators of the CFTR Cl^- channel.