Inhibition of the human two‐pore domain potassium channel, TREK‐1, by fluoxetine and its metabolite norfluoxetine

Abstract

Block of the human two‐pore domain potassium (2‐PK) channel TREK‐1 by fluoxetine (Prozac R) and its active metabolite, norfluoxetine, was investigated using whole‐cell patch‐clamp recording of currents through recombinant channels in tsA 201 cells. Fluoxetine produced a concentration‐dependent inhibition of TREK‐1 current that was reversible on wash. The IC 50 for block was 19 μM. Block by fluoxetine was voltage‐independent. Fluoxetine (100 μM) produced an 84% inhibition of TREK‐1 currents, but only a 31% block of currents through a related 2‐PK channel, TASK‐3. Norfluoxetine was a more potent inhibitor of TREK‐1 currents with an IC 50 of 9 μM. Block by norfluoxetine was also voltage‐independent. Truncation of the C‐terminus of TREK‐1 (Δ89) resulted in a loss of channel function, which could be restored by intracellular acidification or the mutation E306A. The mutation E306A alone increased basal TREK‐1 current and resulted in a loss of the slow phase of TREK‐1 activation. Progressive deletion of the C‐terminus of TREK‐1 had no effect on the inhibition of the channel by fluoxetine. The E306A mutation, on the other hand, reduced the magnitude of fluoxetine inhibition, with 100 μM producing only a 40% inhibition. It is concluded that fluoxetine and norfluoxetine are potent inhibitors of TREK‐1. Block of TREK‐1 by fluoxetine may have important consequences when the drug is used clinically in the treatment of depression. British Journal of Pharmacology (2005) 144, 821–829. doi:10.1038/sj.bjp.0706068