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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca~(2+) channel and the type 1 ryanodine receptor
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Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca~(2+) channel and the type 1 ryanodine receptor

机译：骨骼肌L型Ca〜（2+）通道与1型ryanodine受体之间的静止偶联改变引起的恶性高热敏感性

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摘要

Malignant hyperthermia (MH) susceptibility is a dominantly inherited disorder in which volatile anesthetics trigger aberrant Ca~(2+) release in skeletal muscle and a potentially fatal rise in perioperative body temperature. Mutations causing MH susceptibility have been identified in two proteins critical for excitation-contraction (EC) coupling, the type 1 ryanodine receptor (RyR1) and Ca_v1.1, the principal subunit of the L-type Ca~(2+) channel. All of the mutations that have been characterized previously augment EC coupling and/or increase the rate of L-type Ca~(2+) entry. The Ca_v1.1 mutation R174W associated with MH susceptibility occurs at the innermost basic residue of the IS4 voltage-sensing helix, a residue conserved among all Ca_v channels [Carpenter D, et al. (2009) BMCMed Genet 10:104-115.]. To define the functional consequences of this mutation, we expressed it in dysgenic (Ca_v1.1 null) myotubes. Unlike previously described MH-linked mutations in Ca_v1.1, R174W ablated the L-type current and had no effect on EC coupling. Nonetheless, R174W increased sensitivity of Ca~(2+) release to caffeine (used for MH diagnostic in vitro testing) and to volatile anesthetics. Moreover, in Ca_v1-1 R174W-expressing myotubes, resting myoplasmic Ca~(2+) levels were elevated, and sarco-plasmic reticulum (SR) stores were partially depleted, compared with myotubes expressing wild-type Ca_v1.1. Our results indicate that Ca_v1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting RyRI-mediated Ca~(2+) leak from the SR, and that perturbation of Ca_v1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensitize muscle cells to MH triggers.
机译：恶性高热（MH）易感性是一种遗传性疾病，其中挥发性麻醉药会触发骨骼肌中异常的Ca〜（2+）释放，并可能导致围手术期体温升高致命。已经在两个对激发收缩（EC）耦合至关重要的蛋白质中鉴定出引起MH敏感性的突变，即1型ryanodine受体（RyR1）和Ca_v1.1，这是L型Ca〜（2+）通道的主要亚基。先前已表征的所有突变均增强了EC偶联和/或提高了L型Ca〜（2+）进入的速率。与MH敏感性相关的Ca_v1.1突变R174W发生在IS4电压感应螺旋的最内层碱性残基上，该残基在所有Ca_v通道之间都保守[Carpenter D，等。 （2009）BMCMed Genet 10：104-115。]。为了定义此突变的功能后果，我们在致胚性（Ca_v1.1 null）肌管中表达了该突变。与先前描述的Ca_v1.1中的MH连锁突变不同，R174W消除了L型电流，并且对EC偶联没有影响。尽管如此，R174W增加了Ca〜（2+）释放对咖啡因（用于MH诊断体外测试）和挥发性麻醉剂的敏感性。此外，与表达野生型Ca_v1.1的肌管相比，在表达Ca_v1-1 R174W的肌管中，静息的肌质Ca〜（2+）水平升高，肌浆网（SR）储存被部分耗尽。我们的结果表明，Ca_v1.1不仅在EC耦合过程中激活RyR1，而且还抑制了SR引起的静止RyRI介导的Ca〜（2+）泄漏，并且Ca_v1.1对RyR1泄漏的负调控扰动表明可使肌肉细胞对MH触发敏感的独特机制。

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    Jose Miguel Eltit; Roger A. Bannister; Ong Moua; Francisco Altamirano; Philip M. Hopkins; Isaac N. Pessah; Tadeusz F. Molinski; Jose R. L6pez; Kurt G. Beam; Paul D. Allen;

  • 作者单位

    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115,Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298;

    Cardiology Division, Department of Medicine,and School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO 80045;

    Department of Physiology and Biophysics, School of Medicine, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO 80045;

    Centro de Estudios Moleculares de la Celula, Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile 8380453;

    Malignant Hyperthermia Investigation Unit, Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds LS9 7TF, United Kingdom;

    Department of Molecular Biosciences, Center for Children's Environmental Health and Disease Prevention, School of Veterinary Medicine, University of California, Davis, CA 95616;

    Department of Chemistry and Biochemistry and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, CA 92093;

    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

    Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA 23298;

    Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115;

  • 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

    1,4-dihydropyridine receptor; α_(ls);

    机译：1,4-二氢吡啶受体;α_（ls）;

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