Large-conductance K+ channel openers NS1619 and NS004 as inhibitors of mitochondrial function in glioma cells

被引:69
作者
Debska, G
Kicinska, A
Dobrucki, J
Dworakowska, B
Nurowska, E
Skalska, J
Dolowy, K
Szewczyk, A
机构
[1] M Nencki Inst Expt Biol, Lab Intracellular Ion Channels, PL-02096 Warsaw, Poland
[2] Jagiellonian Univ, Dept Biophys, Lab Confocal Microscopy & Image Anal, PL-31120 Krakow, Poland
[3] Agr Univ Warsaw, Dept Biophys, SGGW, PL-02528 Warsaw, Poland
关键词
glioma cells; mitochondria; respiratory chain; ion channels; potassium channel openers; charybdotoxin;
D O I
10.1016/S0006-2952(03)00180-1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Recently, it has been reported that large-conductance Ca2+-activated potassium channels, also known as BKCa-type potassium channels, are present in the inner mitochondrial membrane of the human glioma LN229 cell line. Hence, in the present study, we have investigated whether BKCa-channel openers (BKCaCOs), such as the benzimidazolone derivatives NS004 (5-trifluoromethyl-1-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benzimidazole-2-one) and NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one), affect the functioning of LN229 glioma cell mitochondria in situ. We examined the effect of BKCaCOs on mitochondrial membrane potential, mitochondrial respiration and plasma membrane potassium current in human glioma cell line LN229. We found that BKCaCOs decrease the mitochondrial membrane potential with an EC50 value of 3.6 +/- 0.4 muM for NS1619 and 5.4 +/- 0.8 muM for NS004. This mitochondrial depolarization was accompanied by an inhibition of the mitochondrial respiratory chain. Both BKCaCOS induced whole-cell potassium current blocked by charybdotoxin, as measured by the patch-clamp technique. The BKCaCOs had no effect on membrane bilayer conductance. Moreover, the inhibition of mitochondrial function by NS004 and NS1619 was without effect on cell survival, as measured by lactate dehydrogenase release from the cells. (C) 2003 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:1827 / 1834
页数:8
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