Antipsychotics inhibit TREK but not TRAAK channels
Section snippets
Methods
COS cells were seeded at a density of 20,000 cells/35-mm dish 24 h before transfection. Cells were transiently transfected by the classical DEAE-dextran method with hTREK-1, hTREK-2 or hTRAAK plasmids and co-transfected with EYFP, a fluorescent marker. Transfected cells were visualized 48–72 h after transfection using fluorescence.
For whole-cell and outside-out experiments the bath solution (EXT) contained (in mM): 150 NaCl, 5 KCl, 1 CaCl2, 3 MgCl2, and 10 Hepes, adjusted to pH 7.4 with NaOH; the
Results
In a first set of experiments we studied the effect of antipsychotic drugs on whole-cell TREK-1 currents. We tested different antipsychotics which can be classified by their chemical structure.
All but substituted benzamides significantly inhibited whole-cell TREK-1 currents at a concentration of 10 μM (Figs. 1A and 4). Inhibition of TREK-1 currents was not voltage-dependent and did not result in a modification of current kinetics (Fig. 1A). The phenothiazines fluphenazine and chlorpromazine (10
Discussion
We have shown that the TREK-1 and TREK-2 background potassium channel can be inhibited by several ‘typical’ and ‘atypical’ antipsychotic drugs with IC50 values of ∼1 to ∼20 μM. The TRAAK channel is not inhibited by antipsychotics at drug concentrations that potently block TREK channel activity. TREK and TRAAK channels are close members of the K2P channel family [3]. Both TREK and TRAAK channels are activated by polyunsaturated fatty acids and by membrane stretch. However, only TREK channels can
Acknowledgments
S.T. received a postdoctoral fellowship of the Deutsche Forschungsgemeinschaft (DFG) and Fondation pour la Recherche Médicale (FRM). This work was supported by the Institut Paul Hamel. We thank A. Patel and G. Sandoz for TREK and TRAAK plasmids and M. Jodar for excellent technical assistance.
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