Large-conductance K+ channel openers NS1619 and NS004 as inhibitors of mitochondrial function in glioma cells
Large-conductance K+ channel openers NS1619 and NS004 as inhibitors of mitochondrial function in glioma cells
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DOI：
10.1016/s0006-2952(03)00180-1
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发表时间：
2003-06-01
影响因子：
5.8
通讯作者：
Szewczyk, A
中科院分区：
文献类型：
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作者：
Debska, G;Kicinska, A;Szewczyk, A
最近有报道称，人胶质瘤LN229细胞系的线粒体内膜中存在大电导Ca2+激活的钾通道，也称为BKCa型钾通道。因此，在本研究中，我们研究了 BKCa 通道开放剂 (BKCaCOs)，例如苯并咪唑酮衍生物 NS004（5-三氟甲基-1-(5-氯-2-羟基苯基)-1,3-二氢-2H-苯并咪唑-2-酮）和 NS1619 (1,3-二氢-1-[2-羟基-5-(三氟甲基)苯基]-5-(三氟甲基)-2H-苯并咪唑-2-酮)，影响 LN229 胶质瘤细胞线粒体的原位功能。我们研究了 BKCaCOs 对人胶质瘤细胞系 LN229 中线粒体膜电位、线粒体呼吸和质膜钾电流的影响。我们发现 BKCaCO 会降低线粒体膜电位，NS1619 的 EC50 值为 3.6 +/- 0.4 muM，NS004 的 EC50 值为 5.4 +/- 0.8 muM。这种线粒体去极化伴随着线粒体呼吸链的抑制。通过膜片钳技术测量，两种 BKCaCOS 均诱导全细胞钾电流被 Charybdotoxin 阻断。 BKCaCO 对膜双层电导没有影响。此外，通过细胞释放乳酸脱氢酶来测量，NS004和NS1619对线粒体功能的抑制对细胞存活没有影响。 (C) 2003 Elsevier Science Inc. 保留所有权利。
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.