Zheng Jingjing, Ponce-Balbuena Daniela, Ríos Pérez Erick B, Xiao Li, Dooge Holly C, Valdivia Héctor H, Alvarado Francisco J
Department of Medicine, Division of Cardiovascular Medicine, and Cardiovascular Research Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, USA.
Nat Cardiovasc Res. 2025 Aug;4(8):976-990. doi: 10.1038/s44161-025-00693-3. Epub 2025 Aug 12.
Phosphorylation of specific sites in ryanodine receptor 2 (RyR2), a major cardiac Ca channel, increases channel activity and promotes pathological sarcoplasmic reticulum Ca leak and arrhythmia. RyR2 is phosphorylated during adrenergic stimulation, but the role of this phosphorylation remains debated. In this study, we generated a mouse model with phospho-ablation of the three canonical phosphorylation sites in RyR2 (S2031A/S2808A/S2814A, triple phospho-mutant (TPM)) to determine their role in the adrenergic response. TPM mice have normal basal cardiac structure and function. Isoproterenol stimulation produced normal chronotropic and inotropic responses in TPM mice and cardiomyocytes, which also showed reduced RyR2-mediated Ca leak. However, TPM mice were susceptible to cardiac arrhythmias. These arrhythmias required systolic Ca release and were induced by the reactivation of I and early afterdepolarizations. We propose that phosphorylation of these residues in RyR2 is dispensable for chronotropy and inotropy; however, they maintain electrical stability during adrenergic stimulation by modulating a physiological RyR2-mediated Ca leak.
兰尼碱受体2（RyR2）是一种主要的心脏钙通道，其特定位点的磷酸化会增加通道活性，并促进病理性肌浆网钙泄漏和心律失常。RyR2在肾上腺素能刺激过程中会发生磷酸化，但其磷酸化作用仍存在争议。在本研究中，我们构建了一种小鼠模型，使RyR2中的三个典型磷酸化位点发生磷酸化缺失（S2031A/S2808A/S2814A，三重磷酸化突变体（TPM）），以确定它们在肾上腺素能反应中的作用。TPM小鼠具有正常的基础心脏结构和功能。异丙肾上腺素刺激在TPM小鼠和心肌细胞中产生了正常的变时性和变力性反应，同时也显示出RyR2介导的钙泄漏减少。然而，TPM小鼠易患心律失常。这些心律失常需要收缩期钙释放，并由I的重新激活和早期后去极化诱导。我们认为，RyR2中这些残基的磷酸化对于变时性和变力性并非必需；然而，它们通过调节生理性RyR2介导的钙泄漏，在肾上腺素能刺激期间维持电稳定性。
