CaMKII in Sinus Node Physiology and Disease

摘要 令人兴奋的最新证据支持这样一种观点，即窦房结（SAN）心脏起搏细胞导致 通过增强肌浆网（SR）Ca 2+释放和增加 肌膜Na+/Ca 2+交换器（NCX）携带的去极化内向电流。专用蛋白质 在收缩的心肌细胞中保持兴奋-收缩偶联和细胞Ca 2+循环 在SAN细胞中，我们的研究表明SAN细胞和心室肌细胞具有相似的SR Ca 2+含量， 指数的细胞膜电容，尽管事实上，SAN细胞表现出最小的机械 活动多功能钙离子和钙调蛋白依赖性蛋白激酶II（CaMKII）是一种丝氨酸- 调节SR相关Ca 2+稳态蛋白受磷蛋白（PLN）的苏氨酸激酶 和Ryanodine受体（RyR）。我们的新数据支持这样一种观点，即CaMKII在细胞凋亡中起着核心作用。 肾上腺素能受体（AR）介导SAN的“战斗或逃跑”生理反应。此外，根据 在过度的病理性AR刺激条件下，CaMKII抑制增强SAN细胞存活 并防止SAN心律失常。我们假设1）CaMKII调节SR Ca 2+摄取， 释放作为生理SAN对AR刺激的反应的细胞机制的一部分; 2）CaMKII 抑制通过阻止SR Ca 2+而保护SAN心律失常、SAN细胞死亡和肥大 内向NCX电流是激活的主要肌膜靶点 通过SR Ca 2+释放，导致增强的4相细胞膜去极化和更快的心率。 我们的实验室已经适应并开发了可靠分离小鼠和兔SAN的新方法 细胞，并进行体内病毒基因转移到SAN和体外病毒基因转移到培养的 SAN细胞。这些创新的方法将使我们能够全面测试CaMKII，SR Ca 2+和NCX在心脏起搏中的作用

Abstract Exciting recent evidence supports a view that sinoatrial node (SAN) cardiac pacemaker cells cause heart rate increases by enhancement of sarcoplasmic reticulum (SR) Ca2+ release and augmentation of depolarizing inward current carried by the sarcolemmal Na+/Ca2+ exchanger (NCX). Proteins dedicated to excitation-contraction coupling and cellular Ca2+ cycling in contracting cardiomyocytes are preserved in SAN cells, and our studies show SAN cells and ventricular myocytes have similar SR Ca2+ content, indexed for cell membrane capacitance, despite the fact that SAN cells exhibit minimal mechanical activity. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is a serine- threonine kinase that regulates the SR-associated Ca2+ homeostatic proteins, phospholamban (PLN) and ryanodine receptors (RyR). Our new data support a view that CaMKII plays a central role in ¿ adrenergic receptor (¿AR) mediated SAN 'fight or flight' physiological responses. Furthermore, under conditions of excessive, pathological ¿AR stimulation, CaMKII inhibition enhances SAN cell survival and protects against SAN arrhythmias. We hypothesize that 1) CaMKII regulates SR Ca2+ uptake and release as part of a cellular mechanism for physiological SAN responses to ¿AR stimulation; 2) CaMKII inhibition protects against SAN arrhythmias, SAN cell death and hypertrophy by preventing SR Ca2+ overload and reducing SR Ca2+ leak; 3) inward NCX current is the major sarcolemmal target activated by SR Ca2+ release, leading to enhanced phase 4 cell membrane depolarization and faster heart rates. Our laboratory has adapted and developed new methods for reliably isolating mouse and rabbit SAN cells, and performing in vivo viral gene transfer to the SAN and in vitro viral gene transfer to cultured SAN cells. These innovative approaches will allow us to comprehensively test the role of CaMKII, SR Ca2+ and NCX in cardiac pacing.