Kennard, L.E. and Chumbley, JR and Ranatunga, KM and Armstrong, SJ and Veale, E.L. and Mathie, A.A. (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. 821-829. ISSN 0007-1188 .
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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.
|Uncontrolled keywords:||two-pore domain potassium channel; TASK-3; TREK-1; fluoxetine; norfluoxetine; C-terminus; potassium current|
|Subjects:||Q Science > QP Physiology (Living systems)|
|Divisions:||Faculties > Science Technology and Medical Studies > Medway School of Pharmacy|
|Depositing User:||Alistair Mathie|
|Date Deposited:||15 Mar 2009 18:20|
|Last Modified:||14 Jan 2010 14:21|
|Resource URI:||http://kar.kent.ac.uk/id/eprint/5638 (The current URI for this page, for reference purposes)|
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