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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Ablation of triadin causes loss of cardiac Ca~(2+) release units, impaired excitation-contraction coupling, and cardiac arrhythmias
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Ablation of triadin causes loss of cardiac Ca~(2+) release units, impaired excitation-contraction coupling, and cardiac arrhythmias

机译：Triadin的消融会导致心脏Ca〜（2+）释放单元的丧失，兴奋收缩耦合受损和心律不齐

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摘要

Heart muscle excitation-contraction (E-C) coupling is governed by Ca~(2+) release units (CRUs) whereby Ca~(2+) influx via L-type Ca~(2+) channels (Cav1.2) triggers Ca~(2+) release from juxtaposed Ca~(2+) release channels (RyR2) located in junctional sarcoplasmic reticu-lum (jSR). Although studies suggest that the jSR protein triadin anchors cardiac calsequestrin (Casq2) to RyR2, its contribution to E-C coupling remains unclear. Here, we identify the role of triadin using mice with ablation of the Trdn gene (Trdn~(-/-)). The structure and protein composition of the cardiac CRU is significantly altered in Trdn~(-/-) hearts. jSR proteins (RyR2, Casq2, junctin, and juncto-philin 1 and 2) are significantly reduced in Trdn~(-/-) hearts, whereas Cav1.2 and SERCA2a remain unchanged. Electron microscopy shows fragmentation and an overall 50% reduction in the contacts between jSR and T-tubules. Immunolabeling experiments show reduced colocalization of Cav1.2 with RyR2 and substantial Casq2 labeling outside of the jSR in Trdn~(-/-) myocytes. CRU function is impaired in Trdn~(-/-) myocytes, with reduced SR Ca~(2+) release and impaired negative feedback of SR Ca~(2+) release on Cav1.2 Ca~(2+) currents (l_(Ca)). Uninhibited Ca~(2+) influx via l_(Ca) likely contributes to Ca~(2+) overload and results in spontaneous SR Ca~(2+) releases upon β-adrenergic receptor stimulation with isoproterenol in Trdn ~(-/-) myocytes, and ventricular arrhythmias in Trdn~(-/-) mice. We conclude that triadin is critically important for maintaining the structural and functional integrity of the cardiac CRU; triadin loss and the resulting alterations in CRU structure and protein composition impairs E-C coupling and renders hearts susceptible to ventricular arrhythmias.
机译：心肌兴奋收缩（EC）耦合受Ca〜（2+）释放单元（CRU）的控制，因此Ca〜（2+）通过L型Ca〜（2+）通道（Cav1.2）流入触发Ca〜（2+） （2+）从并置的肌浆网（jSR）中并列的Ca〜（2+）释放通道（RyR2）释放。尽管研究表明jSR蛋白三联蛋白将心脏钙螯蛋白（Casq2）锚定到RyR2，但其对E-C偶联的作用仍不清楚。在这里，我们确定Triadin的作用与消灭Trdn基因（Trdn〜（-/-））的小鼠。 Trdn〜（-/-）心脏中心脏CRU的结构和蛋白质组成发生了显着变化。 Trdn〜（-/-）心脏中的jSR蛋白（RyR2，Casq2，junctin和junctophilin 1和2）显着减少，而Cav1.2和SERCA2a保持不变。电子显微镜显示，jSR和T管之间的接触破裂并总体减少了50％。免疫标记实验显示，Trdn〜（-/-）心肌细胞中Cav1.2与RyR2的共定位减少，并且在jSR外部有大量Casq2标记。 Trdn〜（-/-）心肌细胞中CRU功能受损，SR Ca〜（2+）释放减少，并且在Cav1.2 Ca〜（2+）电流下SR Ca〜（2+）释放的负反馈受损（l_ （Ca））。经由l_（Ca）不受抑制的Ca〜（2+）流入可能导致Ca〜（2+）超载并导致自发性SR在Trdn〜（-/-）中用异丙肾上腺素刺激β-肾上腺素受体时，Ca〜（2+）释放。 ）和Trdn〜（-/-）小鼠的心肌细胞和室性心律失常。我们得出结论，三联蛋白对于维持心脏CRU的结构和功能完整性至关重要。三联蛋白的损失以及由此导致的CRU结构和蛋白质组成的改变会损害E-C偶联，并使心脏容易患心律失常。

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  • 作者

    Nagesh Chopra; Tao Yang; Parisa Asghari; Edwin D. Moore; Sabine Huke; Brandy Akin; Robert A. Cattolica; Claudio F. Perez; Thinn Hlaing; Barbara E. C. Knollmann-Ritschel; Larry R. Jones; Isaac N. Pessah; Paul D. Allen; Clara Franzini-Armstrong; Bjoern C. Knollmann;

  • 作者单位

    Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;

    Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;

    Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Department of Medicine, Krannert Institute of Cardiology, Indiana University, Indianapolis, IN 46202;

    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616;

    Department of Anesthesia, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115;

    Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37232 Department of Medicine, University of Miami, Miami, FL 33136;

    Department of Pathology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814;

    Department of Medicine, Krannert Institute of Cardiology, Indiana University, Indianapolis, IN 46202;

    Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616;

    Department of Anesthesia, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115;

    Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA 19104;

    Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Vanderbilt University, Nashville, TN 37232;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    cardiac muscle; sarcoplasmic reticulum; calsequestrin; cav1.2; RyR2;

    机译：心肌;肌浆网钙蛋白cav1.2;RyR2;

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