Lin Meng Chin A, Papazian Diane M
Department of Physiology and Molecular Biology Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1751, USA.
Channels (Austin). 2007 Nov-Dec;1(6):429-37. doi: 10.4161/chan.1.6.5760. Epub 2008 Feb 19.
HERG (KCNH2) and ether-à-go-go (eag) (KCNH1) are members of the same subfamily of voltage-gated K+ channels. In eag, voltage-dependent activation is significantly slowed by extracellular divalent cations. To exert this effect, ions bind to a site located between transmembrane segments S2 and S3 in the voltage sensor domain where they interact with acidic residues that are conserved only among members of the eag subfamily. In HERG channels, extracellular divalent ions significantly accelerate deactivation. To investigate the ionbinding site in HERG, acidic residues in S2 and S3 were neutralized singly or in pairs to alanine, and the functional effects of extracellular Mg(2+) were characterized in Xenopus oocytes. To modulate deactivation kinetics in HERG, divalent cations interact with eag subfamily-specific acidic residues (D460 and D509) and also with an acidic residue in S2 (D456) that is widely conserved in the voltage-gated channel superfamily. In contrast, the analogous widely-conserved residue does not contribute to the ion-binding site that modulates activation kinetics in eag. We propose that structural differences between the ion-binding sites in the eag and HERG voltage sensors contribute to the differential regulation of activation and deactivation gating in these channels. A previously proposed model for S4 conformational changes during voltagedependent activation can account for the differential regulation of gating seen in eag and HERG.
HERG（KCNH2）和去极化激活钾通道（eag）（KCNH1）是电压门控钾通道同一家族的成员。在eag通道中，细胞外二价阳离子会显著减缓电压依赖性激活。为发挥这种作用，离子结合到电压感受器结构域中跨膜片段S2和S3之间的一个位点，在那里它们与仅在eag家族成员中保守的酸性残基相互作用。在HERG通道中，细胞外二价离子会显著加速失活。为研究HERG中的离子结合位点，将S2和S3中的酸性残基单个或成对突变为丙氨酸，并在非洲爪蟾卵母细胞中表征细胞外Mg(2+)的功能效应。为调节HERG中的失活动力学，二价阳离子与eag家族特异性酸性残基（D460和D509）相互作用，还与S2中的一个酸性残基（D456）相互作用，该残基在电压门控通道超家族中广泛保守。相比之下，类似的广泛保守残基对调节eag中激活动力学的离子结合位点没有贡献。我们提出，eag和HERG电压感受器中离子结合位点的结构差异导致了这些通道中激活和失活门控的差异调节。先前提出的一个关于电压依赖性激活过程中S4构象变化的模型可以解释在eag和HERG中观察到的门控差异调节。
