Uchinoumi Hitoshi, Nakamura Yoshihide, Suetomi Takeshi, Nawata Takashi, Fujinaka Masafumi, Kobayashi Shigeki, Yamamoto Takeshi, Yano Masafumi, Sano Motoaki
Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan.
J Cardiol. 2025 Feb 8. doi: 10.1016/j.jjcc.2025.02.003.
The type 2 ryanodine receptor (RyR2) is a giant Ca (Ca)-releasing channel on the sarcoplasmic reticulum (SR) membrane, with subunits composed of 5000 amino acids constituting a homotetrameric channel. The N-terminal (1-220) and central (2300-2500) domain interactions (inter-subunit zipping interfaces) within RyR2 are located in close proximity to each other between different neighboring subunits and play an important "cornerstone" role in maintaining the tetrameric structure of RyR2. External stress such as oxidative stress causes Ca leak by destabilizing RyR2 (instability of the tetrameric structure) due to domain unzipping between N-terminal (1-220) and central (2300-2500) domains, followed by dissociation of calmodulin (CaM: binds to the RyR2 and stabilize RyR2) from RyR2. Ca leak from SR causes arrhythmias and myocardial dysfunction. RyR2 is also present in the endoplasmic reticulum (ER), thus it is not surprising that undesired Ca release from RyR2 on the ER is closely associated with various diseases involving ER dysfunction such as neurodegenerative diseases, diabetes, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, and autoimmune diseases. Pharmacological or genetic (point mutations within RyR2 that increase CaM-RyR2 affinity: knock-in RyR2-V3599K) RyR2 structural stabilization has shown potential therapeutic effects not only for SR failure-related diseases (malignant hyperthermia, arrhythmia, and heart failure) but also for ER failure-related disease. RyR2-stabilizers may function as a panacea for aging-related diseases.
2型兰尼碱受体（RyR2）是肌浆网（SR）膜上的一种巨大的钙（Ca）释放通道，其亚基由5000个氨基酸组成，构成一个同四聚体通道。RyR2内的N端（1 - 220）和中央（2300 - 2500）结构域相互作用（亚基间拉链界面）在不同相邻亚基之间彼此紧邻，在维持RyR2的四聚体结构中起重要的“基石”作用。诸如氧化应激等外部应激通过使N端（1 - 220）和中央（2300 - 2500）结构域之间的结构域解拉链而使RyR2不稳定（四聚体结构不稳定），从而导致Ca泄漏，随后钙调蛋白（CaM：与RyR2结合并稳定RyR2）从RyR2上解离。SR的Ca泄漏会导致心律失常和心肌功能障碍。RyR2也存在于内质网（ER）中，因此，内质网上RyR2意外的Ca释放与各种涉及内质网功能障碍的疾病密切相关就不足为奇了，这些疾病包括神经退行性疾病、糖尿病、代谢功能障碍相关脂肪性肝病、慢性肾病和自身免疫性疾病。药理学或遗传学方法（RyR2内增加CaM - RyR2亲和力的点突变：敲入RyR2 - V3599K）使RyR2结构稳定不仅对与SR功能衰竭相关的疾病（恶性高热、心律失常和心力衰竭）显示出潜在治疗效果，而且对与ER功能衰竭相关的疾病也有效果。RyR2稳定剂可能是治疗衰老相关疾病的万灵药。
