Notch signaling modulates the electrical behavior of cardiomyocytes
Notch signaling modulates the electrical behavior of cardiomyocytes
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DOI：
10.1152/ajpheart.00587.2016
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发表时间：
2018-01-01
影响因子：
4.8
通讯作者：
Rota, Marcello
中科院分区：
文献类型：
--
作者：
Borghetti, Giulia;Eisenberg, Carol A.;Rota, Marcello
Notch受体信号在心脏发育过程中活跃，出生后在肌细胞中沉默。相反，向外的K+ Kv电流逐渐出现在出生后的肌细胞中，导致动作电位（AP）缩短并获得成熟的电表型。在本研究中，我们测试了Notch信号通过干扰Kv电流来调节心肌细胞电行为的可能性。为此，利用诱导表达Notch1细胞内结构域（NICD）（激活的Notch受体的功能片段）的转基因小鼠，以及抑制Notch转导途径后的新生儿肌细胞，研究了Notch受体活性对肌细胞电生理特性的影响。通过膜片钳，与野生型小鼠相比，nicd过表达的细胞表现出延长的AP持续时间和减少的上冲程振幅，这些特性与快速激活Kv和快速Na+电流的减少相结合。在培养的新生儿肌细胞中，用γ -分泌酶拮抗剂抑制NICD的蛋白化释放可增加Kv通道相互作用蛋白2 （KChIP2）的转录水平，并增强Kv电流的密度。总的来说，这些结果表明Notch信号通过抑制（至少部分地）重极化Kv电流，代表了发育和成年肌细胞电生理行为的重要调节因子。我们研究了Notch受体信号传导对心肌细胞电特性的影响。我们的研究结果表明，Notch转导通路干扰向外K+ Kv电流，这是肌细胞电复极化的关键决定因素。
Notch receptor signaling is active during cardiac development and silenced in myocytes after birth. Conversely, outward K+ Kv currents progressively appear in postnatal myocytes leading to shortening of the action potential (AP) and acquisition of the mature electrical phenotype. In the present study, we tested the possibility that Notch signaling modulates the electrical behavior of cardiomyocytes by interfering with Kv currents. For this purpose, the effects of Notch receptor activity on electrophysiological properties of myocytes were evaluated using transgenic mice with inducible expression of the Notch1 intracellular domain (NICD), the functional fragment of the activated Notch receptor, and in neonatal myocytes after inhibition of the Notch transduction pathway. By patch clamp, NICD-overexpressing cells presented prolonged AP duration and reduced upstroke amplitude, properties that were coupled with reduced rapidly activating Kv and fast Na+ currents, compared with cells obtained from wild-type mice. In cultured neonatal myocytes, inhibition of the proteolitic release of NICD with a gamma-secretase antagonist increased transcript levels of the Kv channel-interacting proteins 2 (KChIP2) and enhanced the density of Kv currents. Collectively, these results indicate that Notch signaling represents an important regulator of the electrophysiological behavior of developing and adult myocytes by repressing, at least in part, repolarizing Kv currents.NEW & NOTEWORTHY We investigated the effects of Notch receptor signaling on the electrical properties of cardiomyocytes. Our results indicate that the Notch transduction pathway interferes with outward K+ Kv currents, critical determinants of the electrical repolarization of myocytes.