hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: A possible mechanism for long QT syndrome
hERG1a N-terminal eag domain-containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: A possible mechanism for long QT syndrome
复制标题
DOI：
10.1085/jgp.201110683
复制
发表时间：
2011-12-01
影响因子：
3.8
通讯作者：
Robertson, Gail A.
中科院分区：
文献类型：
--
作者：
Trudeau, Matthew C.;Leung, Lisa M.;Robertson, Gail A.
人类ether-a-go-go-related gene（hERG）钾通道对心脏动作电位复极至关重要。心脏hERG通道包括两种主要亚型：hERG 1a，具有调节性N末端Per-Arnt-Sim（PAS）结构域，hERG 1b，没有。分离的含PAS的hERG 1a N-末端区域（NTRs）直接调节NTRs缺失的hERG 1a通道;然而，目前尚不清楚hERG 1b亚型是否包含足够的机制来支持hERG 1a NTRs的调节。为了验证这一点，我们构建了一系列含有PAS结构域的hERG 1a NTR（编码氨基酸1-181、1-228、1-319和1-365）。NTR也被预测是由与2型长QT综合征（LQTS）相关的截短突变形成的，2型长QT综合征是一种与hERG基因突变相关的心脏疾病。所有的hERG 1a NTR显着调节异源hERG 1a/hERG 1b通道和同源hERG 1b通道，通过降低电流-电压关系的幅度和减缓通道关闭（失活）的动力学。相比之下，NTR没有可测量地调节hERG 1a通道。主要由PAS结构域组成的短NTR（编码氨基酸1-135）足以调节hERG 1b。这些结果表明，分离的hERG 1a NTR直接与hERG 1b亚基相互作用。我们的研究结果表明，hERG 1a/hERG 1b通道的失活速度比hERG 1a通道快，因为PAS结构域较少，而不是因为独特的hERG 1b NTR的抑制作用。hERG 1a NTR降低hERG 1a/hERG 1b通道的外向电流密度可能是LQTS的一种机制。
Human ether-a-go-go-related gene (hERG) potassium channels are critical for cardiac action potential repolarization. Cardiac hERG channels comprise two primary isoforms: hERG1a, which has a regulatory N-terminal Per-Arnt-Sim (PAS) domain, and hERG1b, which does not. Isolated, PAS-containing hERG1a N-terminal regions (NTRs) directly regulate NTR-deleted hERG1a channels; however, it is unclear whether hERG1b isoforms contain sufficient machinery to support regulation by hERG1a NTRs. To test this, we constructed a series of PAS domain-containing hERG1a NTRs (encoding amino acids 1-181, 1-228, 1-319, and 1-365). The NTRs were also predicted to form from truncation mutations that were linked to type 2 long QT syndrome (LQTS), a cardiac arrhythmiadisorder associated with mutations in the hERG gene. All of the hERG1a NTRs markedly regulated heteromeric hERG1a/hERG1b channels and homomeric hERG1b channels by decreasing the magnitude of the current-voltage relationship and slowing the kinetics of channel closing (deactivation). In contrast, NTRs did not measurably regulate hERG1a channels. A short NTR (encoding amino acids 1-135) composed primarily of the PAS domain was sufficient to regulate hERG1b. These results suggest that isolated hERG1a NTRs directly interact with hERG1b subunits. Our results demonstrate that deactivation is faster in hERG1a/hERG1b channels compared to hERG1a channels because of fewer PAS domains, not because of an inhibitory effect of the unique hERG1b NTR. A decrease in outward current density of hERG1a/hERG1b channels by hERG1a NTRs may be a mechanism for LQTS.