Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel.
Cohesin-protein Shugoshin-1 controls cardiac automaticity via HCN4 pacemaker channel.
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DOI：
10.1038/s41467-021-22737-5
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发表时间：
2021-05-05
影响因子：
16.6
通讯作者：
Nattel S
中科院分区：
文献类型：
--
作者：
Liu D;Song AT;Qi X;van Vliet PP;Xiao J;Xiong F;Andelfinger G;Nattel S
内源性心脏起搏器功能调节心脏收缩的速率和节律。黏连蛋白Shugoshin-1中的突变p.Lys23Glu导致严重的心律失常，这是由于窦房结功能障碍和衰弱性胃肠动力障碍，统称为慢性心房和肠节律障碍综合征，将Shugoshin-1和起搏器活动联系起来。超极化激活的环核苷酸门控阳离子通道4（HCN 4）是成人心脏中主要的起搏离子通道，并携带大部分“有趣”电流，这对起搏细胞的舒张期去极化有很大贡献。在这里，我们研究Shugoshin-1影响心脏起搏活动的机制与两个细胞模型：新生大鼠心室肌细胞和慢性心房和肠节律障碍综合征患者特异性的人诱导多能干细胞衍生的心肌细胞。我们发现Shugoshin-1直接与HCN 4相互作用，以促进和稳定心脏起搏。这种相互作用通过优化HCN 4细胞表面表达和功能来增强滑稽电流。临床p.Lys23Glu突变导致Shugoshin-1和HCN 4之间相互作用的损害，沿着来自慢性心房和肠节律障碍综合征患者的诱导多能干细胞衍生的心肌细胞中的抑制的滑稽电流和节律障碍活动。我们的工作揭示了Shugoshin-1在维持心脏自律性方面的关键非经典，非粘附素依赖性作用，并确定了心脏起搏障碍，特别是慢性心房和肠节律障碍综合征的潜在治疗途径。Shugoshin-1的突变导致慢性心房和肠节律障碍（CAID）综合征，但其潜在机制尚不清楚。在这里，作者表明，Shugoshin-1通过与HCN 4相互作用以增强其细胞表面表达来控制心脏起搏器活动，并且CAID综合征突变通过干扰这种重要的非经典相互作用来破坏心脏起搏。
Endogenous cardiac pacemaker function regulates the rate and rhythm of cardiac contraction. The mutation p.Lys23Glu in the cohesin protein Shugoshin-1 causes severe heart arrhythmias due to sinoatrial node dysfunction and a debilitating gastrointestinal motility disorder, collectively termed the Chronic Atrial and Intestinal Dysrhythmia Syndrome, linking Shugoshin-1 and pacemaker activity. Hyperpolarization-activated, cyclic nucleotide-gated cation channel 4 (HCN4) is the predominant pacemaker ion-channel in the adult heart and carries the majority of the “funny” current, which strongly contributes to diastolic depolarization in pacemaker cells. Here, we study the mechanism by which Shugoshin-1 affects cardiac pacing activity with two cell models: neonatal rat ventricular myocytes and Chronic Atrial and Intestinal Dysrhythmia Syndrome patient-specific human induced pluripotent stem cell derived cardiomyocytes. We find that Shugoshin-1 interacts directly with HCN4 to promote and stabilize cardiac pacing. This interaction enhances funny-current by optimizing HCN4 cell-surface expression and function. The clinical p.Lys23Glu mutation leads to an impairment in the interaction between Shugoshin-1 and HCN4, along with depressed funny-current and dysrhythmic activity in induced pluripotent stem cell derived cardiomyocytes derived from Chronic Atrial and Intestinal Dysrhythmia Syndrome patients. Our work reveals a critical non-canonical, cohesin-independent role for Shugoshin-1 in maintaining cardiac automaticity and identifies potential therapeutic avenues for cardiac pacemaking disorders, in particular Chronic Atrial and Intestinal Dysrhythmia Syndrome. A mutation in Shugoshin-1 causes the Chronic Atrial and Intestinal Dysrhythmia (CAID) Syndrome, but the underlying mechanisms are unknown. Here, the authors show that Shugoshin-1 controls cardiac pacemaker activity by interacting with HCN4 to enhance its cell-surface expression, and that the CAID-Syndrome mutation disrupts cardiac pacemaking by interfering with this important non-canonical interaction.
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影响因子：
5
作者：
Kim, Jong J.;Yang, Lei;Lin, Bo;Zhu, Xiaodong;Sun, Bin;Kaplan, Aaron D.;Bett, Glenna C. L.;Rasmusson, Randall L.;London, Barry;Salama, Guy
通讯作者：
Salama, Guy
影响因子：
64.8
作者：
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影响因子：
64.8
作者：
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通讯作者：
Watanabe, Y
影响因子：
64.8
作者：
Itzhaki, Ilanit;Maizels, Leonid;Gepstein, Lior
通讯作者：
Gepstein, Lior
影响因子：
37.8
作者：
Er, F;Larbig, R;Hoppe, UC
通讯作者：
Hoppe, UC