Vinogradova Tatiana M, Lakatta Edward G
Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, National Institute of Health, Baltimore, MD 21224, USA.
Cells. 2024 Dec 25;14(1):3. doi: 10.3390/cells14010003.
The spontaneous firing of the sinoatrial (SA) node, the physiological pacemaker of the heart, is generated within sinoatrial nodal cells (SANCs) and is regulated by a "coupled-clock" pacemaker system, which integrates a "membrane clock", the ensemble of ion channel currents, and an intracellular "Ca clock", sarcoplasmic reticulum-generated local submembrane Ca releases via ryanodine receptors. The interactions within a "coupled-clock" system are modulated by phosphorylation of surface membrane and sarcoplasmic reticulum proteins. Though the essential role of a high basal cAMP level and PKA-dependent phosphorylation for basal spontaneous SANC firing is well recognized, the role of basal CaMKII-dependent phosphorylation remains uncertain. This is a critical issue with respect to how cardiac pacemaker cells fire spontaneous action potentials. This review aspires to explain and unite apparently contradictory results of pharmacological studies in the literature that have demonstrated a fundamental role of basal CaMKII activation for basal cardiac pacemaker function, as well as studies in mice with genetic CaMKII inhibition which have been interpreted to indicate that basal spontaneous SANC firing is independent of CaMKII activation. The assessment of supporting and opposing data regarding CaMKII effects on phosphorylation of Ca-cycling proteins and spontaneous firing of SANC in the basal state leads to the necessary conclusion that CaMKII activity and CaMKII-dependent phosphorylation do regulate basal cardiac pacemaker function.
心脏的生理起搏器——窦房（SA）结的自发放电在窦房结细胞（SANCs）内产生，并受“耦合时钟”起搏器系统调节，该系统整合了“膜时钟”（离子通道电流的集合）和细胞内“钙时钟”（肌浆网通过兰尼碱受体产生的局部膜下钙释放）。“耦合时钟”系统内的相互作用通过表面膜和肌浆网蛋白的磷酸化进行调节。尽管高基础cAMP水平和PKA依赖性磷酸化对基础窦房结细胞自发放电的重要作用已得到充分认识，但基础CaMKII依赖性磷酸化的作用仍不确定。这是一个关于心脏起搏器细胞如何产生自发动作电位的关键问题。本综述旨在解释并统一文献中药理学研究的明显矛盾结果，这些研究表明基础CaMKII激活对基础心脏起搏器功能具有重要作用，同时也包括对基因敲除CaMKII的小鼠的研究，这些研究被解释为表明基础窦房结细胞自发放电独立于CaMKII激活。对关于CaMKII对钙循环蛋白磷酸化和基础状态下窦房结细胞自发放电影响的支持和反对数据的评估得出了必然结论，即CaMKII活性和CaMKII依赖性磷酸化确实调节基础心脏起搏器功能。
