KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging
KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging
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DOI：
10.1073/pnas.0609278104
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发表时间：
2007-03-06
影响因子：
11.1
通讯作者：
Bodmer, Rolf
中科院分区：
文献类型：
--
作者：
Ocorr, Karen;Reeves, Nick L.;Bodmer, Rolf
工业化国家的人口分布显示，随着年龄的增长，心血管疾病急剧增加，但由于缺乏合适的模型系统，疾病进展的分子和遗传基础一直难以研究。我们对果蝇的研究表明，在衰老的果蝇心脏中，心功能障碍和心律失常的发生率显著升高，同时果蝇同源的人类kcnq1编码的K+通道α亚基的表达减少。在人类中，该通道参与心肌复极，该通道功能的改变与扭转型心律失常和猝死的风险增加有关。年轻的KCNQ1突变果蝇的心脏表现出长时间的收缩和纤颤，让人联想到Torsades des Pointes心律失常，并且它们在年轻时表现出对起搏诱导的心功能障碍的严重易感性，这些特征仅在老年的WT果蝇中观察到。在突变果蝇中观察到的纤颤与延迟的心肌松弛相关，这可以通过增加相性收缩的持续时间、细胞外场电位和基线舒张张力来揭示。这些结果表明，KCNQ通道介导的K+电流有助于果蝇心脏的复极化储备，确保正常的兴奋-收缩耦合和节律性收缩。随着果蝇年龄的增长，WT和KCNQ1突变体的心律失常都变得更糟，这表明还有其他因素参与其中。
Population profiles of industrialized countries show dramatic increases in cardiovascular disease with age, but the molecular and genetic basis of disease progression has been difficult to study because of the lack of suitable model systems. Our studies of Drosophila show a markedly elevated incidence of cardiac dysfunction and arrhythmias in aging fruit fly hearts and a concomitant decrease in the expression of the Drosophila homolog of human KCNQ1-encoded K+ channel alpha subunits. in humans, this channel is involved in myocardial repolarization, and alterations in the function of this channel are associated with an increased risk for Torsades des Pointes arrhythmias and sudden death. Hearts from young KCNQ1 mutant fruit flies exhibit prolonged contractions and fibrillations reminiscent of Torsades des Pointes arrhythmias, and they exhibit severely increased susceptibility to pacing-induced cardiac dysfunction at young ages, characteristics that are observed only at advanced ages in WT flies. The fibrillations observed in mutant flies correlate with delayed relaxation of the myocardium, as revealed by increases in the duration of phasic contractions, extracellular field potentials, and in the baseline diastolic tension. These results suggest that K+ currents, mediated by a KCNQ channel, contribute to the repolarization reserve of fly hearts, ensuring normal excitation-contraction coupling and rhythmical contraction. That arrhythmias in both WT and KCNQ1 mutants become worse as flies age suggests that additional factors are also involved.