Antipsychotics inhibit TREK but not TRAAK channels

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Abstract

Schizophrenia is a chronic mental illness affecting 0.4% of the population. Existing antipsychotic drugs are mainly used to treat positive symptoms such as hallucinations but have only poor effects on negative symptoms such as cognitive deficits or depression. TREK and TRAAK channels are two P domain background potassium channels activated by polyunsaturated fatty acids and mechanical stress. TREK but not TRAAK channels are regulated by Gs- and Gq-coupled pathways. The inactivation of the TREK-1 but not the TRAAK channel in mice results in a depression-resistant phenotype. In addition, it has been shown that antidepressants such as fluoxetine or paroxetine directly inhibit TREK channel activity. Here we show that different antipsychotic drugs directly inhibit TREK currents with IC50 values of ∼1 to ∼20 μM. No effect is seen on TRAAK channel activity. We conclude that TREK channels might be involved in the therapeutic action of antipsychotics or in their secondary effects. Furthermore, TREK channels could play a role in the pathophysiology of psychiatric disorders such as depression and schizophrenia.

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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