On the importance of ryanodine receptor subunit cooperativity in the heart.
On the importance of ryanodine receptor subunit cooperativity in the heart.
复制标题
关于兰尼碱受体亚基协同作用在心脏中的重要性。
DOI：
10.1016/j.bpj.2022.11.016
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发表时间：
2023
影响因子：
3.4
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Zhang X
心肌细胞内钙稳态是心肌收缩和电生理功能的重要决定因素，并通过钙诱导的钙释放（CICR）过程负责兴奋收缩偶联。心肌细胞含有促进快速和稳健的CICR的细胞内结构：2型兰尼碱受体（RyR），负责从细胞内Ca 2+库（肌浆网）释放Ca 2+，以簇的形式分布在整个细胞内体积中，与肌膜和驻留在其中的L型Ca 2+通道紧密并列（< 20 nm），形成二联体（1）。RyR功能障碍可能直接损害CICR，从而损害兴奋收缩偶联，导致细胞收缩受到抑制或效率低下;此外，许多实验报告表明，RyR特征的变化是与各种疾病相关的心律失常的主要因素，如房颤（2）和心力衰竭（3）。为了理解RyR在多个尺度（即从分子到器官水平）的作用，需要对RyR在健康和疾病中的动力学进行生理学上准确的数学描述，理想的RyR模型不仅应该复制RyR动力学的实验观察，而且应该在Ca 2+稳态的亚细胞或细胞水平计算模型的多个相互作用组分的背景下稳健地进行。多个成熟的（二态、三态和四态）RyR Markov模型通常用于复制RyR动力学（即开放、关闭、失活和不应期）和收缩/舒张期Ca 2+调节（例如肌浆网渗漏、Ca 2+火花和Ca 2+波）。所有模型的设计复制RyR动力学和Ca 2+动态功能的一部分，但可以参数化用于不同的目的，例如，保持稳定的Ca 2+稳态或再现自发的Ca 2+火花在适当的频率。尽管RyR动力学对细胞功能至关重要，但RyR的数学描述的发展仍然是一个重大挑战，它既可以从实验通道观察中确定，又可以同时稳健地再现生理和病理生理行为的全部范围。
Intracellular calcium (Ca2+) homeostasis in cardiac myocytes is an important determinant of both contractile and electrophysiological function and is responsible for excitation contraction coupling through the process of Ca2+-induced Ca2+ release (CICR). Cardiomyocytes contain an intracellular structure that facilitates rapid and robust CICR: type 2 ryanodine receptors (RyRs), responsible for Ca2+ release from the intracellular Ca2+ store, the sarcoplasmic reticulum, are distributed throughout the intracellular volume in clusters closely juxtaposed (< 20 nm) with the sarcolemmal membrane and the L-type Ca2+ channels that reside therein, forming dyads (1). RyR dysfunction may directly impair CICR and thus excitation contraction coupling, resulting in inhibited or inefficient cellular contraction; moreover, many experimental reports have indicated that a change of RyR characteristics is a major contributor to arrhythmia associated with various conditions, such as atrial fibrillation (2) and heart failure (3). To understand the role of RyRs at multiple scales (ie, from molecular-to organ-level), a physiologically accurate mathematical description of RyR kinetics in health and disease is needed.An ideal RyR model should not only replicate the experimental observations of RyR kinetics but also conduct robustly in the context of the multiple interacting components of the subcellular or cell-level computational models of Ca2+ homeostasis. Multiple well-established (two-, three-, and four-state) RyR Markov models have been commonly used to replicate RyR kinetics (ie, opening, closing, inactivation, and refractoriness) and systolic/diastolic Ca2+ regulation (eg, sarcoplasmic reticulum leak, Ca2+ sparks, and Ca2+ waves). All the models are designed to replicate part of the RyR kinetics and Ca2+ dynamic features but may be parameterized for different purposes, eg, maintaining stable Ca2+ homeostasis or reproducing spontaneous Ca2+ sparks at appropriate frequency. Despite the fundamental importance of RyR dynamics for cellular function, the development of a mathematical description of the RyR, which is both determined from experimental channel observations and simultaneously robustly reproduces the full range of physiological and pathophysiological behaviors, remains a major challenge (4).