尼氟酸对与去极化激活的钾离子通道相关基因钾通道亚型依赖性激活的结构基础。

Structural basis for ether-a-go-go-related gene K+ channel subtype-dependent activation by niflumic acid.

作者信息

Fernandez David, Sargent John, Sachse Frank B, Sanguinetti Michael C

机构信息

Nora Eccles Harrison Cardiovascular Research and Training Institute, Department of Physiology, University of Utah, 95 South 2000 East, Salt Lake City, UT 84112, USA.

出版信息

Mol Pharmacol. 2008 Apr;73(4):1159-67. doi: 10.1124/mol.107.043505. Epub 2008 Jan 24.

Niflumic acid [2-((3-(trifluoromethyl)phenyl)amino)-3-pyridinecarboxylic acid, NFA] is a nonsteroidal anti-inflammatory drug that also blocks or modulates the gating of a wide spectrum of ion channels. Here we investigated the mechanism of channel activation by NFA on ether-a-go-go-related gene (ERG) K(+) channel subtypes expressed in Xenopus laevis oocytes using two-electrode voltage-clamp techniques. NFA acted from the extracellular side of the membrane to differentially enhance ERG channel currents independent of channel state. At 1 mM, NFA shifted the half-point for activation by -6, -18, and -11 mV for ERG1, ERG2, and ERG3 channels, respectively. The half-point for channel inactivation was shifted by +5 to +9 mV by NFA. The structural basis for the ERG subtype-specific response to NFA was explored with chimeric channels and site-directed mutagenesis. The molecular determinants of enhanced sensitivity of ERG2 channels to NFA were isolated to an Arg and a Thr triplet in the extracellular S3-S4 linker.

尼氟灭酸[2-((3-(三氟甲基)苯基)氨基)-3-吡啶羧酸，NFA]是一种非甾体抗炎药，它还能阻断或调节多种离子通道的门控。在此，我们使用双电极电压钳技术，研究了NFA对非洲爪蟾卵母细胞中表达的醚-去极化相关基因(ERG)钾通道亚型的通道激活机制。NFA从细胞膜的外侧起作用，以差异方式增强ERG通道电流，而与通道状态无关。在1 mM时，NFA分别使ERG1、ERG2和ERG3通道的激活中点向负方向移动了-6、-18和-11 mV。通道失活的中点被NFA向正方向移动了+5至+9 mV。我们用嵌合通道和定点诱变技术探索了ERG亚型对NFA特异性反应的结构基础。ERG2通道对NFA敏感性增强的分子决定因素被定位在细胞外S3-S4连接区的一个精氨酸和一个苏氨酸三联体上。