Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor
Malignant hyperthermia susceptibility arising from altered resting coupling between the skeletal muscle L-type Ca2+ channel and the type 1 ryanodine receptor
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DOI：
10.1073/pnas.1119207109
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发表时间：
2012-05-15
影响因子：
11.1
通讯作者：
Allen, Paul D.
中科院分区：
文献类型：
--
作者：
Eltit, Jose Miguel;Bannister, Roger A.;Allen, Paul D.
恶性高热（MH）易感性是一种显性遗传性疾病，其中挥发性麻醉剂触发骨骼肌中异常Ca 2+释放和围手术期体温可能致命的升高。在兴奋-收缩（EC）偶联的两种关键蛋白质中，即1型兰尼碱受体（RyR 1）和L型Ca 2+通道的主要亚基Ca（V）1.1中，已鉴定出引起MH易感性的突变。所有的突变，以前已被表征增强EC耦合和/或增加L型Ca 2+进入的速率。与MH易感性相关的Ca（V）1.1突变R174 W发生在IS 4电压敏感螺旋的最内侧碱性残基处，该残基在所有Ca-V通道中是保守的[ Carpenter D，et al.（2009）BMC Med Genet 10：104-115.]。为了确定这种突变的功能后果，我们在基因缺陷（Ca（V）1.1 null）肌管中表达了它。与之前描述的Ca（V）1.1中MH相关突变不同，R174 W消融了L型电流，并且对EC偶联没有影响。尽管如此，R174 W增加了Ca 2+释放对咖啡因（用于MH诊断体外试验）和挥发性麻醉剂的敏感性。此外，与表达野生型Ca（V）1.1的肌管相比，在Ca（V）1.1 R174 W表达的肌管中，静息肌浆Ca 2+水平升高，肌浆网（SR）储存部分耗尽。我们的研究结果表明，Ca（V）1.1的功能不仅激活RyR 1在EC耦合，但也抑制静息RyR 1介导的Ca 2+泄漏从SR，和扰动的Ca（V）1.1的负调控RyR 1泄漏确定了一个独特的机制，可以敏感的肌肉细胞MH触发。
Malignant hyperthermia (MH) susceptibility is a dominantly inherited disorder in which volatile anesthetics trigger aberrant Ca2+ release in skeletal muscle and a potentially fatal rise in peri-operative 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(V)1.1, the principal subunit of the L-type Ca2+ channel. All of the mutations that have been characterized previously augment EC coupling and/or increase the rate of L-type Ca2+ entry. The Ca(V)1.1 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) BMC Med Genet 10:104-115.]. To define the functional consequences of this mutation, we expressed it in dysgenic (Ca(V)1.1 null) myotubes. Unlike previously described MH-linked mutations in Ca(V)1.1, R174W ablated the L-type current and had no effect on EC coupling. Nonetheless, R174W increased sensitivity of Ca2+ release to caffeine (used for MH diagnostic in vitro testing) and to volatile anesthetics. Moreover, in Ca(V)1.1 R174W-expressing myotubes, resting myoplasmic Ca2+ levels were elevated, and sarcoplasmic reticulum (SR) stores were partially depleted, compared with myotubes expressing wild-type Ca(V)1.1. Our results indicate that Ca(V)1.1 functions not only to activate RyR1 during EC coupling, but also to suppress resting RyR1-mediated Ca2+ leak from the SR, and that perturbation of Ca(V)1.1 negative regulation of RyR1 leak identifies a unique mechanism that can sensitize muscle cells to MH triggers.