PDF(Pubmed)
Abstract：
Introduction: Ca2+ levels in adult skeletal muscle fibers are mainly controlled by excitation-contraction (EC) coupling, a mechanism that translates action potentials in release of Ca2+ from the sarcoplasmic reticulum (SR) release channels, i.e. the ryanodine receptors type-1 (RyR1). Calsequestrin (Casq) is a protein that binds large amounts of Ca2+ in the lumen of the SR terminal cisternae, near sites of Ca2+ release. There is general agreement that Casq is not only important for the SR ability to store Ca2+, but also for modulating the opening probability of the RyR Ca2+ release channels. The initial studies: About 20 years ago we generated a mouse model lacking Casq1 (Casq1-null mice), the isoform predominantly expressed in adult fast twitch skeletal muscle. While the knockout was not lethal as expected, lack of Casq1 caused a striking remodeling of membranes of SR and of transverse tubules (TTs), and mitochondrial damage. Functionally, CASQ1-knockout resulted in reduced SR Ca2+ content, smaller Ca2+ transients, and severe SR depletion during repetitive stimulation. The myopathic phenotype of Casq1-null mice: After the initial studies, we discovered that Casq1-null mice were prone to sudden death when exposed to halogenated anaesthetics, heat and even strenuous exercise. These syndromes are similar to human malignant hyperthermia susceptibility (MHS) and environmental-exertional heat stroke (HS). We learned that mechanisms underlying these syndromes involved excessive SR Ca2+ leak and excessive production of oxidative species: indeed, mortality and mitochondrial damage were significantly prevented by administration of antioxidants and reduction of oxidative stress. Though, how Casq1-null mice could survive without the most important SR Ca2+ binding protein was a puzzling issue that was not solved. Unravelling the mystery: The mystery was finally solved in 2020, when we discovered that in Casq1-null mice the SR undergoes adaptations that result in constitutively active store-operated Ca2+ entry (SOCE). SOCE is a mechanism that allows skeletal fibers to use external Ca2+ when SR stores are depleted. The post-natal compensatory mechanism that allows Casq1-null mice to survive involves the assembly of new SR-TT junctions (named Ca2+ entry units) containing Stim1 and Orai1, the two proteins that mediate SOCE.
摘要：
简介：成人骨骼肌纤维中的Ca2+水平主要受兴奋-收缩（EC）耦合控制，一种从肌浆网（SR）释放通道中释放Ca2+的动作电位的机制，即ryanodine受体1型(RyR1)。Calsequestrin（Casq）是一种与SR末端水箱内腔中大量Ca2结合的蛋白质，在Ca2+释放位点附近。人们普遍认为，Casq不仅对SR存储Ca2+的能力很重要，还用于调节RyRCa2+释放通道的开放概率。初步研究：大约20年前，我们产生了一个缺乏Casq1的小鼠模型（Casq1-null小鼠），同工型主要在成年快肌骨骼肌中表达。虽然淘汰赛不像预期的那样致命，缺乏Casq1导致SR膜和横小管（TT）的显着重塑，和线粒体损伤。功能上,CASQ1敲除导致SRCa2+含量降低，更小的Ca2+瞬变，重复刺激期间严重的SR耗竭。Casq1-null小鼠的肌病表型：经过初步研究，我们发现Casq1-null小鼠在暴露于卤化麻醉剂时容易突然死亡，热甚至剧烈运动。这些综合征类似于人类恶性高热易感性（MHS）和环境劳力性中暑（HS）。我们了解到，这些综合征的潜在机制涉及过度的SRCa2泄漏和过度的氧化物质产生：确实，通过施用抗氧化剂和减少氧化应激,可以显著预防死亡率和线粒体损伤.不过,Casq1-null小鼠如何在没有最重要的SRCa2+结合蛋白的情况下生存是一个令人困惑的问题，没有解决。解开谜团：这个谜团终于在2020年得到解决，当时我们发现在Casq1-null小鼠中，SR经历了适应，导致组成性活跃的存储操作Ca2进入（SOCE）。SOCE是一种当SR存储耗尽时允许骨骼纤维使用外部Ca2+的机制。允许Casq1-null小鼠存活的出生后代偿机制涉及包含Stim1和Orai1这两种介导SOCE的蛋白质的新SR-TT连接（称为Ca2进入单位）的组装。
