心肌收缩通过与位于细丝上的异源三聚体肌钙蛋白复合物的Ca2交换来调节。Ca2+与心肌肌钙蛋白C的结合,肌钙蛋白复合物中的Ca2+传感亚基,导致细丝组件之间的一系列构象重排,导致肌动球蛋白交叉桥和肌肉收缩的形成增加。最终,细胞内Ca2+的下降导致Ca2+从肌钙蛋白C中解离,抑制跨桥循环和启动肌肉松弛。因此,肌钙蛋白C在调节心肌收缩和舒张中起着至关重要的作用。肌钙蛋白C中天然存在的和工程化的突变可导致细丝的组分之间的相互作用改变,并导致与细丝的异常Ca2+结合和交换。肌钙蛋白C的突变与各种形式的心脏病有关,包括肥厚,限制性的,扩张,和左心室心肌致密化不全。尽管迄今为止取得了进展,更多来自人类研究的信息,生物物理表征,需要动物模型来更清楚地了解导致心肌病的疾病驱动因素。具有L48Q突变的工程化心脏肌钙蛋白C的独特使用已被彻底表征并遗传地引入小鼠心肌中,清楚地表明Ca2+敏化本身不一定被认为是疾病驱动因素。这为小分子和蛋白质工程策略打开了大门,以帮助增强受损的收缩功能。另一方面,工程肌钙蛋白C突变体(I61Q和D73N),基因导入小鼠心肌,证明在基础条件下Ca2脱敏可能是扩张型心肌病的驱动因素。除了增强我们对引发肥大的分子机制的认识,膨胀,发病率,和死亡率,这些心肌病小鼠模型可用于测试心血管疾病的新治疗策略.在这次审查中,我们将讨论(1)心脏肌钙蛋白C突变可能导致疾病的各种方式;(2)心脏肌钙蛋白C突变与人类疾病相关的相关数据,和(3)所有目前存在的含有心肌肌钙蛋白C突变的小鼠模型(疾病相关和工程)。
Cardiac muscle contraction is regulated via Ca2+ exchange with the hetero-trimeric troponin complex located on the thin filament. Binding of Ca2+ to cardiac troponin C, a Ca2+ sensing subunit within the troponin complex, results in a series of conformational re-arrangements among the thin filament components, leading to an increase in the formation of actomyosin cross-bridges and muscle contraction. Ultimately, a decline in intracellular Ca2+ leads to the dissociation of Ca2+ from troponin C, inhibiting cross-bridge cycling and initiating muscle relaxation. Therefore, troponin C plays a crucial role in the regulation of cardiac muscle contraction and relaxation. Naturally occurring and engineered mutations in troponin C can lead to altered interactions among components of the thin filament and to aberrant Ca2+ binding and exchange with the thin filament. Mutations in troponin C have been associated with various forms of cardiac disease, including hypertrophic, restrictive, dilated, and left ventricular noncompaction cardiomyopathies. Despite progress made to date, more information from human studies, biophysical characterizations, and animal models is required for a clearer understanding of disease drivers that lead to cardiomyopathies. The unique use of engineered cardiac troponin C with the L48Q mutation that had been thoroughly characterized and genetically introduced into mouse myocardium clearly demonstrates that Ca2+ sensitization in and of itself should not necessarily be considered a disease driver. This opens the door for small molecule and protein engineering strategies to help boost impaired systolic function. On the other hand, the engineered troponin C mutants (I61Q and D73N), genetically introduced into mouse myocardium, demonstrate that Ca2+ desensitization under basal conditions may be a driving factor for dilated cardiomyopathy. In addition to enhancing our knowledge of molecular mechanisms that trigger hypertrophy, dilation, morbidity, and mortality, these cardiomyopathy mouse models could be used to test novel treatment strategies for cardiovascular diseases. In this review, we will discuss (1) the various ways mutations in cardiac troponin C might lead to disease; (2) relevant data on mutations in cardiac troponin C linked to human disease, and (3) all currently existing mouse models containing cardiac troponin C mutations (disease-associated and engineered).