Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability
Cx43 hemichannel microdomain signaling at the intercalated disc enhances cardiac excitability
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DOI：
10.1172/jci137752
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发表时间：
2021-04-01
影响因子：
15.9
通讯作者：
Leybaert, Luc
中科院分区：
文献类型：
--
作者：
De Smet, Maarten A. J.;Lissoni, Alessio;Leybaert, Luc
Cx43是一种主要的心脏连接蛋白，形成前体半通道，在闰盘处聚集成间隙连接。虽然间隙连接对于心脏中的电传导至关重要，但对半通道的潜在作用知之甚少。最近的证据表明，用Gap19抑制Cx43半通道开放具有抗肿瘤作用。在这里，我们使用多种电生理学，成像和超分辨率技术来理解和定义心室心肌细胞中Cx43半通道激活的基础条件，它们对肌浆网舒张期Ca2+释放的贡献，以及它们对电稳定性的影响。我们发现，Cx43半通道被激活舒张期钙释放在单个心室心肌细胞和心肌细胞对从小鼠和猪。这种激活涉及Cx43半通道Ca2+进入并耦合到闰盘处的Ca2+释放微区，导致增强的Ca2+动力学。半通道开放还有助于延迟后除极和触发动作电位。在单个心肌细胞，心肌细胞对，和动脉灌注组织楔从失败的人心脏，增加半通道活动促成了电不稳定性相比，nonfail拒绝供体心脏。我们的结论是，Cx43半通道和Ca2+释放之间的微区耦合是一个潜在的新的，有针对性的机制心力衰竭的心脏血管生成。
Cx43, a major cardiac connexin, forms precursor hemichannels that accrue at the intercalated disc to assemble as gap junctions. While gap junctions are crucial for electrical conduction in the heart, little is known about the potential roles of hemichannels. Recent evidence suggests that inhibiting Cx43 hemichannel opening with Gap19 has antiarrhythmic effects. Here, we used multiple electrophysiology, imaging, and super-resolution techniques to understand and define the conditions underlying Cx43 hemichannel activation in ventricular cardiomyocytes, their contribution to diastolic Ca2+ release from the sarcoplasmic reticulum, and their impact on electrical stability. We showed that Cx43 hemichannels were activated during diastolic Ca2+ release in single ventricular cardiomyocytes and cardiomyocyte cell pairs from mice and pigs. This activation involved Cx43 hemichannel Ca2+ entry and coupling to Ca2+ release microdomains at the intercalated disc, resulting in enhanced Ca2+ dynamics. Hemichannel opening furthermore contributed to delayed afterdepolarizations and triggered action potentials. In single cardiomyocytes, cardiomyocyte cell pairs, and arterially perfused tissue wedges from failing human hearts, increased hemichannel activity contributed to electrical instability compared with nonfailing rejected donor hearts. We conclude that microdomain coupling between Cx43 hemichannels and Ca2+ release is a potentially novel, targetable mechanism of cardiac arrhythmogenesis in heart failure.