Progress in the Intracellular Clock that Drives the Heart's Pacemaker

驱动心脏起搏器的细胞内时钟的进展

• 批准号: 7592070
• 负责人: Edward G Lakatta
• 金额: $ 159万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592070
• 关键词: Acceleration; Achievement; Adult; Artificial cardiac pacemaker; Biochemical; Calcium; Cardiac; Cells; Characteristics; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Databases; Embryo; Goals; Heart; Image; Ion Channel; Kinetics; Length; Mediating; Membrane; Methodology; Muscle Cells; Nodal; Oryctolagus cuniculus; Pacemakers; Periodicity; Phosphorylation; Protein Isoforms; Proteins; Rate; Recovery; Regulation; Research; Role; Shapes; Surface; System; Ventricular; afterpotential; base; cell type; feeding; phosphoric diester hydrolase; theories

LCS studies of pacemaker function have generated the idea that, as reviewed here, normal automaticity of SANC results from the mutual entrainment of an internal Ca2+ clock and surface membrane ion channel clock. In short, The Ca2+ clock in rabbit SANC is driven by high basal level of cAMP. Constitutive activation of b-ARs is not present within SANC. Rather, SANC express AC isoforms that are Ca2+ activated (AC1&8), permitting Ca2+ releases to act as a feed forward system to control SANC beating: Ca2+ activation of AC increases cAMP which activates PKA resulting in phosphorylation of Ca2+ cycling proteins and an acceleration of the Ca2+ clock. A markedly elevated basal PDE activity within SANC acts as brake to limit the cAMP level and the extent of cAMP-dependent phosphorylation of Ca2+ cycling proteins regulates LCRs characteristics and maintains basal beating rate well below maximum level. In other words, PKA dependent phosphorylation regulates kinetics of SR Ca2+ cycling and also determines the constitutive activity of ACs (activated by Ca2+), which, in turn, increases cAMP and PKA and thus determines the periodicity of LCRs, which in turn, determines the spontaneous SANC cycle length. Graded inhibition of PKA activity results in graded reduction of Ca2+ cycling protein phosphorylation, graded slowing of the Ca2+ clock (prolongation of LCR period) and graded reduction of the spontaneous beating rate 4.As noted, evidence regarding control of basal cAMP mediated PKA dependent Ca2+ cycling protein phosphorylation that drives spontaneous beating of SANC has begun to emerge. Based on our extensive database presented here, we suggest a new, relatively simple interpretation of the entire DD shape, a major problem of the cardiac pacemaker field since its discovery. The Ca2+ clock initiates each pacemaker cycle by igniting a subsequent AP via DD acceleration. The MDP, followed by early slow DD, are in fact components of an afterpotential, i.e. recovery of ion channels from previous AP. The evidence for the crucial role of Ca2+ and rhythmic spontaneous Ca2+ releases in the initiation and regulation of normal cardiac automaticity both in adult and embryonic pacemaker cells also provides the key that reunites pacemaker and ventricular cell research 32, 35. The separate achievements of reductionist approaches to elucidate how strength of contraction of ventricular myocytes and the spontaneous beating rate of pacemaker cells are regulated now converge: Ca2+ cycling into and from the SR by proteins common to both ventricular myocytes and pacemaker cells can be portrayed as Ca2+ clock. The mutual entrainment of the Ca2+ clock and surface membrane ion channel clocks regulate the duty cycle of both cell types. THUS, BASED UPON OUR STUDIES, WE PROPOSE A GENERAL THEORY OF CARDIAC INOTROPY AND CHRONOTROPY.

Pacemaker功能的LCS研究产生了这样的想法，即在此处综述，SANC的正常自动化是由于内部Ca2+时钟和表面膜离子通道时钟相互夹带而产生的。简而言之，兔子Sanc中的Ca2+时钟是由高基底营地驱动的。 SANC中不存在B-AR的组成型激活。相反，Sanc Express AC同工型是Ca2+激活的（AC1和8），允许Ca2+释放充当饲料前进系统以控制SANC跳动：CA2+ AC激活增加了CAMP，这会激活PKA，从而激活PKA，从而导致Ca2+循环蛋白的磷酸化和Ca2+ CA2+时钟的加速。 SANC内的显着升高的基底PDE活性起到了制动作用，可限制CA2+循环蛋白的cAMP依赖性磷酸化的程度，可调节LCR的特性并保持基础跳动率远低于最大水平。 换句话说，PKA依赖性磷酸化调节了SR Ca2+循环的动力学，并且还确定了AC的组成型活性（被Ca2+激活），从而增加了CAMP和PKA，从而确定了LCR的周期性，从而决定了自发性Sanc sanc Cycle Cyceclenth。 Graded inhibition of PKA activity results in graded reduction of Ca2+ cycling protein phosphorylation, graded slowing of the Ca2+ clock (prolongation of LCR period) and graded reduction of the spontaneous beating rate 4.As noted, evidence regarding control of basal cAMP mediated PKA dependent Ca2+ cycling protein phosphorylation that drives spontaneous beating of SANC has begun to emerge. 根据我们此处介绍的广泛数据库，我们建议对整个DD形状进行一种新的，相对简单的解释，这是自发现以来心脏起搏器领域的主要问题。 CA2+时钟通过通过DD加速度点燃随后的AP来启动每个起搏器周期。 MDP随后是早期慢DD，实际上是电阻的组成部分，即从先前的AP恢复离子通道。 Ca2+和节奏自发的Ca2+释放在成人和胚胎过时的起搏器细胞中正常心脏自动化的启动和调节中至关重要的作用的证据也提供了使起搏器和心室细胞研究重新统一的关键32，35。阐明了还原性的分别构成型的跨性别的成就，并具有多余的构成量的跨性别效果。现在调节细胞：CA2+通过与心室心肌细胞和起搏器细胞共有的蛋白质循环和从SR循环，并且可以将Ca2+时钟描绘成CA2+时钟。 Ca2+时钟和表面膜离子通道时钟的相互夹带调节两种细胞类型的占空比。因此，基于我们的研究，我们提出了心脏障碍和年表的一般理论。

项目成果

Cardiac pacemaker cell failure with preserved I(f), I(CaL), and I(Kr): a lesson about pacemaker function learned from ischemia-induced bradycardia.

• DOI: 10.1016/j.yjmcc.2006.11.009
• 发表时间: 2007-02
• 期刊: Journal of molecular and cellular cardiology
• 影响因子: 5
• 作者: V. Maltsev;E. Lakatta

Rhythmic Ca2+ oscillations drive sinoatrial nodal cell pacemaker function to make the heart tick.

有节奏的 Ca2 振荡驱动窦房结细胞起搏器功能，使心脏跳动。

• DOI: 10.1196/annals.1341.013
• 发表时间: 2005
• 期刊: Annals of the New York Academy of Sciences
• 影响因子: 5.2
• 作者: Vinogradova,TatianaM;Maltsev,VictorA;Bogdanov,KonstantinY;Lyashkov,AlexeyE;Lakatta,EdwardG
• 通讯作者: Lakatta,EdwardG