Novel Regulatory Elements within Myofilaments of Vertebrate Striated Muscles-Who Knew.
Novel Regulatory Elements within Myofilaments of Vertebrate Striated Muscles-Who Knew.
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脊椎动物横纹肌肌丝中的新调节元件——谁知道。
DOI：
10.1016/j.bpj.2018.07.043
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发表时间：
2018
影响因子：
3.4
通讯作者：
Moss,RichardL
中科院分区：
文献类型：
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作者：
Moss,RichardL
20世纪肌肉生物学中最有影响力的进展之一是Ebashi和Endo(1)发现了肌钙蛋白，它是脊椎动物横纹肌细丝调节链中的主要钙结合蛋白。这一开创性的报告开启了一个重要的研究领域，最初专注于确定肌钙蛋白的亚基组成，然后逐步高分辨率地研究亚基结构、亚基相互作用以及由于钙离子与肌钙蛋白结合而导致的其中一个或两者的变化(2)。随后该领域关于这种结合在调节肌肉收缩中的可能作用的想法(S)受到了一系列观察的影响，这些观察在这里仅作简要总结，没有限定或归属。例如，肌原纤维ATPase活性在肌钙蛋白存在时随钙离子浓度而变化，但在没有肌钙蛋白时活性最大，不受钙离子影响。结合肌钙蛋白收缩的力量和速度随钙离子浓度变化的发现，这些结果为肌钙蛋白结合的钙离子作为调节细丝激活状态的分级开关的观点提供了实验支持(2)。在其最简单的应用中，由于钙离子与肌钙蛋白结合而导致细丝的开关样激活的概念一直被视为严格的反应过程，在这个过程中，活的肌肉中的跨桥数量、力和功率直接通过改变肌浆网释放的钙离子的量来控制。尽管这种肌丝激活的观点似乎将兴奋-收缩耦合的领域简化为仅仅是兴奋和耦合，但它没有考虑细丝介导的调节中的显著非线性，或者由于粗丝或细丝中调节蛋白的翻译后修饰而引起的调节的变化。例如，钙离子与肌钙蛋白的结合和肌球蛋白与细丝的跨桥结合都存在正的协同性，并且每个过程都动态地加强了另一个过程。当[Ca~(2+)]增加到力发展的最大值时，力发展的动力学速度提高了10倍，这不能用简单的依赖于钙的细丝开关调节来解释。由于力(和功率)和钙离子的传递在骨骼肌中是动态调节的，在心肌中在更大程度上是动态调节的，因此可以合理地假设(但仍难以检验)每个过程的动力学和程度都是动态调整的，以匹配另一个过程。看起来很可能是因为-
Among the most influential advances in muscle biology during the 20th century was the discovery by Ebashi and Endo (1) of troponin, the primary Ca2+-binding protein within the thinfilament regulatory strand of vertebrate striated muscles. This seminal report opened an important field of research that initially focused on determining the subunit composition of troponin and then on progressively higher-resolution studies of subunit structure, subunit interactions, and changes in either or both as a consequence of Ca2+ binding to troponin (2). Subsequent thought in the field about the possible role (s) of such binding in the regulation of muscle contraction has been influenced by a constellation of observations that are summarized only briefly here, without qualification or attribution. For example, myofibrillar ATPase activity varies with Ca2+ concentration in the presence of troponin but is maximal and unaffected by Ca2+ in its absence. Together with findings that contractile force and velocity vary with Ca2+ concentration, these results provided experimental support for the idea that Ca2+ binding by troponin serves as a graded switch regulating the activation state of the thin filament (2).In its simplest application, the notion of switch-like activation of the thin filament due to Ca2+ binding to troponin has been viewed as a strictly responsiveness process in which cross-bridge number, force, and power in living muscle are controlled straightforwardly by varying the amount of Ca2+ released from the sarcoplasmic reticulum. Although this view of myofilament activation appears to have simplified the field of excitation-contraction coupling to just excitation and coupling, it does not take into account the pronounced nonlinearities in thin filament-mediated regulation or variations in regulation due to post-translational modifications of regulatory proteins in the thick or thin filaments. As examples, there is positive cooperativity in the binding of Ca2+ to troponin and in myosin cross-bridge binding to the thin filament, and each process dynamically reinforces the other. And the kinetics of force development are accelerated 10-fold when [Ca2+] is increased from threshold to maximum for force development, which is not explained by a simple Ca2+-dependent on-off regulation of the thin filament. Because force (and power) and Ca2+ delivery are dynamically regulated in skeletal muscle and to a greater degree in cardiac muscle, it is reasonable to presume (but as yet difficult to test) that the kinetics and extent of each process are dynamically tuned to match the other. It seems likely that compen-