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Inhibition of the Human Two-Pore Domain Potassium Channel, Trek-1, by Fluoxetine and Its Metabolite Norfluoxetine

Kennard, Louise E, Chumbley, Justin R, Ranatunga, Kishani M, Armstrong, Stephanie J, Veale, Emma L., Mathie, Alistair (2005) Inhibition of the Human Two-Pore Domain Potassium Channel, Trek-1, by Fluoxetine and Its Metabolite Norfluoxetine. British journal of pharmacology, 144 (6). pp. 821-9. ISSN 0007-1188. (doi:10.1038/sj.bjp.0706068) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:75930)

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1. Block of the human two-pore domain potassium (2-PK) channel TREK-1 by fluoxetine (Prozac) and its active metabolite, norfluoxetine, was investigated using whole-cell patch-clamp recording of currents through recombinant channels in tsA 201 cells. 2. Fluoxetine produced a concentration-dependent inhibition of TREK-1 current that was reversible on wash. The IC50 for block was 19 microM. Block by fluoxetine was voltage-independent. Fluoxetine (100 microM) produced an 84% inhibition of TREK-1 currents, but only a 31% block of currents through a related 2-PK channel, TASK-3. 3. Norfluoxetine was a more potent inhibitor of TREK-1 currents with an IC50 of 9 microM. Block by norfluoxetine was also voltage-independent. 4. Truncation of the C-terminus of TREK-1 (delta89) 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. 5. 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 microM producing only a 40% inhibition. 6. 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.

Item Type: Article
DOI/Identification number: 10.1038/sj.bjp.0706068
Divisions: Divisions > Division of Natural Sciences > Medway School of Pharmacy
Depositing User: Emma Veale
Date Deposited: 21 Aug 2019 12:19 UTC
Last Modified: 16 Nov 2021 10:26 UTC
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