Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation
Altered HCN4 channel C-linker interaction is associated with familial tachycardia-bradycardia syndrome and atrial fibrillation
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DOI：
10.1093/eurheartj/ehs391
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发表时间：
2013-09-01
影响因子：
39.3
通讯作者：
Koenen, Michael
中科院分区：
文献类型：
--
作者：
Duhme, Nana;Schweizer, Patrick A.;Koenen, Michael
目的HCN4通道参与心律的产生、调节和稳定，通道功能障碍与遗传性窦性心动过缓有关。我们询问功能失调的HCN4通道是否也会导致心动过速。方法和结果在候选基因方法中，我们筛选了422例心房和/或室性心动过速患者，并检测到一种新的HCN4基因突变，该突变在c -连接体的高度保守区域用天冬酰胺（HCN4- k530n）取代了带正电的赖氨酸530。该指数患者以年龄依赖的方式发展为心动过速-心动过缓综合征和持续性心房颤动（AF）。系谱分析确定了8名受影响的家庭成员具有相似的病程。HEK293细胞的全细胞膜片钳电生理学研究表明，同源突变通道与野生型通道几乎无法区分。相比之下，由突变型和野生型亚基组成的异质通道在半最大激活电压下表现出明显的超极化位移。这可能是由于HCN4的c端结构域（据信由“二聚体的二聚体”组成）的张力抑制的无核苷酸状态和激活的配体结合的四聚体形式之间的平衡发生了变化，导致对异质通道活性的抑制增加。结论异质通道c连接蛋白寡聚化改变可促进家族性心动过速-心动过缓综合征和持续性房颤的发生，提示f通道功能障碍参与了房性心动过速的发生。
Aims HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to the generation of cardiac tachyarrhythmias.Methods and results In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker. The index patient developed tachycardia-bradycardia syndrome and persistent atrial fibrillation (AF) in an age-dependent fashion. Pedigree analysis identified eight affected family members with a similar course of disease. Whole-cell patch clamp electrophysiology of HEK293 cells showed that homomeric mutant channels almost are indistinguishable from wild-type channels. In contrast, heteromeric channels composed of mutant and wild-type subunits displayed a significant hyperpolarizing shift in the half-maximal activation voltage. This may be caused by a shift in the equilibrium between the tonically inhibited nucleotide-free state of the C-terminal domain of HCN4 believed to consist of a 'dimer of dimers' and the activated ligand-bound tetrameric form, leading to an increased inhibition of activity in heteromeric channels.Conclusion Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF, indicating that f-channel dysfunction contributes to the development of atrial tachyarrhythmias.