Department of Physiology and Cellular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Division of Cardiology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; email:
Annu Rev Physiol. 2022 Feb 10;84:285-306. doi: 10.1146/annurev-physiol-060121-041653. Epub 2021 Nov 9.
Each heartbeat is initiated by the action potential, an electrical signal that depolarizes the plasma membrane and activates a cycle of calcium influx via voltage-gated calcium channels, calcium release via ryanodine receptors, and calcium reuptake and efflux via calcium-ATPase pumps and sodium-calcium exchangers. Agonists of the sympathetic nervous system bind to adrenergic receptors in cardiomyocytes, which, via cascading signal transduction pathways and protein kinase A (PKA), increase the heart rate (chronotropy), the strength of myocardial contraction (inotropy), and the rate of myocardial relaxation (lusitropy). These effects correlate with increased intracellular concentration of calcium, which is required for the augmentation of cardiomyocyte contraction. Despite extensive investigations, the molecular mechanisms underlying sympathetic nervous system regulation of calcium influx in cardiomyocytes have remained elusive over the last 40 years. Recent studies have uncovered the mechanisms underlying this fundamental biologic process, namely that PKA phosphorylates a calcium channel inhibitor, Rad, thereby releasing inhibition and increasing calcium influx. Here, we describe an updated model for how signals from adrenergic agonists are transduced to stimulate calcium influx and contractility in the heart.
每次心跳都是由动作电位引发的，动作电位是一种电信号，使质膜去极化并通过电压门控钙通道激活钙内流循环，通过兰尼碱受体释放钙，通过钙-ATP 酶泵和钠-钙交换器进行钙再摄取和外排。交感神经系统的激动剂与心肌细胞中的肾上腺素能受体结合，通过级联信号转导途径和蛋白激酶 A（PKA），增加心率（变时性）、心肌收缩力（变力性）和心肌松弛率（变力性）。这些效应与细胞内钙离子浓度的增加相关，钙离子是增强心肌收缩所必需的。尽管进行了广泛的研究，但在过去的 40 年中，交感神经系统调节心肌细胞钙离子内流的分子机制仍然难以捉摸。最近的研究揭示了这一基本生物学过程的机制，即 PKA 磷酸化钙通道抑制剂 Rad，从而释放抑制并增加钙离子内流。在这里，我们描述了一个更新的模型，说明来自肾上腺素能激动剂的信号如何被转导，以刺激心脏中的钙离子内流和收缩性。
