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Regulation of TREK1 two pore domain potassium channels by citalopram
Author(s) -
AlMoubarak Ehab,
Veale Emma L,
Mathie Alistair
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.913.31
Subject(s) - citalopram , chemistry , wild type , patch clamp , biophysics , microbiology and biotechnology , pharmacology , biochemistry , biology , gene , receptor , mutant , serotonin
TREK‐1, two pore domain potassium (K2P) channels are responsible for background currents that regulate neuronal excitability. In this study we investigated the effect of the antidepressant, citalopram, on TREK1 channels. tsA‐201 cells were transiently transfected with wild type and mutated K2P channels. The whole cell patch clamp technique was used to obtain current recordings. Homology models for TREK1 were constructed using Modeller. Citalopram was docked to these models using the MOE program. Citalopram (100 μM) significantly inhibited WT TREK1 by 73 ± 2 % (n=8). Docking of citalopram into the TREK1 homology model suggests that it resides in the central cavity of the channel and its binding may involve residues from both the pore regions (T142 & T251) and regions of M2 and M4 (L174 & L289). These residues were mutated to alanine and the inhibitory effect of citalopram was reduced significantly in each case. The E306A gain of function mutation prevented citalopram inhibition. S‐citalopram (n=5) and R‐ citalopram (n=6) were equally effective at inhibiting TREK1. Citalopram (100 μM) was also able to inhibit TREK‐2 (57 ± 3 %, n=8) and TRESK (47 ± 4 %, n=7) but only inhibited TASK3 by 12 ± 5 %. (n=7). These data may explain the association observed between subjects with TREK1 gene variants and citalopram treatment resistance (Perlis et al 2008, Neuropsychopharm 33: 2810). Supported by BBSRC and Pfizer.