Thümmler Susanne, Duprat Fabrice, Lazdunski Michel
Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Université de Nice-Sophia Antipolis, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France.
Biochem Biophys Res Commun. 2007 Mar 2;354(1):284-9. doi: 10.1016/j.bbrc.2006.12.199. Epub 2007 Jan 3.
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 IC(50) values of approximately 1 to approximately 20 microM. 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.
精神分裂症是一种影响0.4%人口的慢性精神疾病。现有的抗精神病药物主要用于治疗幻觉等阳性症状，但对认知缺陷或抑郁等阴性症状效果不佳。TREK和TRAAK通道是两种由多不饱和脂肪酸和机械应力激活的P结构域背景钾通道。TREK通道而非TRAAK通道受Gs和Gq偶联途径调节。小鼠中TREK-1通道而非TRAAK通道的失活导致抗抑郁表型。此外，已表明氟西汀或帕罗西汀等抗抑郁药可直接抑制TREK通道活性。在此我们表明，不同的抗精神病药物可直接抑制TREK电流，半数抑制浓度（IC50）值约为1至约20微摩尔。对TRAAK通道活性无影响。我们得出结论，TREK通道可能参与抗精神病药物的治疗作用或其副作用。此外，TREK通道可能在抑郁症和精神分裂症等精神疾病的病理生理学中起作用。
