Ca²⁺ acts on troponin and tropomyosin to switch the thin filament on and off, however in cardiac muscle a more graded form of regulation is essential to tailor cardiac output to the body’s needs. This is achieved by the action of adrenaline on β1 receptors of heart muscle cells leading to enhanced contractility, faster heart rate and faster relaxation (lusitropy) via activation of the cyclic AMP-dependent protein kinase, PKA. PKA phosphorylates serines 22 and 23 in the N-terminal peptide of cardiac troponin I. As a consequence the rate of Ca²⁺release from troponin is increased. This is the key determinant of lusitropy. The molecular mechanism of this process has remained unknown long after the mechanism of the troponin Ca²⁺ switch itself was defined. Investigation of this subtle process at the atomic level poses a challenge, since the change in Ca²⁺-sensitivity is only about twofold and key parts of the troponin modulation and regulation system are disordered and cannot be fully resolved by conventional structural approaches. We will review recent studies using molecular dynamics simulations together with functional, cryo-em and NMR techniques that have started to give us a precise picture of how phosphorylation of troponin I modulates the dynamics of troponin to produce the lusitropic effect.

Ca ²⁺ 作用于肌钙蛋白和原肌球蛋白以打开和关闭细丝，但在心肌中，更分级的调节形式对于根据身体需要调整心输出量至关重要。这是通过肾上腺素作用于心肌细胞的 β1 受体来实现的，通过激活环 AMP 依赖性蛋白激酶 PKA，从而增强收缩性、加快心率和加快松弛（松弛）。 PKA 磷酸化心肌肌钙蛋白 I N 末端肽中的丝氨酸 22 和 23。结果，肌钙蛋白释放 Ca ²⁺的速率增加。这是松散性的关键决定因素。在肌钙蛋白 Ca ²⁺ 开关本身的机制被定义很久之后，这个过程的分子机制仍然未知。在原子水平上研究这一微妙过程提出了挑战，因为 Ca ²⁺敏感性的变化仅约为两倍，并且肌钙蛋白调制和调节系统的关键部分是无序的，并且无法通过常规结构方法完全解决。我们将回顾最近使用分子动力学模拟以及功能、冷冻电镜和核磁共振技术的研究，这些技术已经开始为我们提供肌钙蛋白 I 磷酸化如何调节肌钙蛋白动力学以产生松弛效应的精确图像。