Progress in the Intracellular Clock that Drives the Hear

LCS科学家的新研究表明，细胞内的？Ca2 +时钟?在SANC内，肌浆网产生有节奏的细胞内自发钙释放，点燃表面膜的兴奋（SCaRIE）。实验证据来自于同时，膜下Ca2+和起搏器细胞的膜电位的共聚焦成像（并得到数值模拟的支持），表明这些细胞的起搏功能被Ca2+时钟的紧密整合所携带和稳定，Ca2+时钟产生有节奏的SCaRIE，表面膜时钟响应SCaRIE，立即产生AP？形状合适的S。因此，严格控制的节律性SCaRIE不仅微调窦房结细胞AP放电，而且是节律性心跳的正式（初始）原因。Ca2+时钟通过有节奏地整合多种Ca2+依赖的功能来确保起搏器的稳定性，并通过有节奏地点燃表面膜时钟来影响正常的自动性。

Novel studies by LCS scientists demonstrate that an intracellular ?Ca2+ clock? within SANC, the sarcoplasmic reticulum, generates rhythmic, intracellular Spontaneous Ca Releases that Ignite Excitation (SCaRIE) of the surface membrane. Experimental evidence, derived from simultaneous, confocal imaging of submembrane Ca2+ and membrane potential of pacemaker cells (and supported by numerical modeling), indicates the pacemaking function of these cells is entrained and stabilized by the tight integration of the Ca2+ Clock that generates rhythmic SCaRIE, and the surface Membrane Clock that responds to SCaRIE, to immediately produce AP?s of an adequate shape. Thus, tightly controlled, rhythmic SCaRIE does not merely fine tune sinoatrial nodal cell AP firing, but is the formal (initiating) cause of the rhythmic heartbeat. The Ca2+ clock insures pacemaker stability by rhythmically integrating multiple Ca2+-dependent functions, and effects normal automaticity by rhythmic ignition of the surface membrane Clock. Cells within the heart?s pacemaker, i.e., sinoatrial nodal cells (SANC), normally ?auto excite? to produce spontaneous action potentials (AP?s). An ensemble of surface membrane ion channels (?Membrane Clock?) determines the instantaneous membrane potential change and is clearly the immediate cause of the spontaneous AP?s. But the idea that the surface Membrane Clock is also a formal, i.e., a primary, or initiating, cause of normal pacemaking function, became dogma that has gripped the pacemaker research field in an ?intellectual and experimental phase lock? for nearly five decades. Thus, the entire, normal duty cycle of pacemaker cells has been portrayed simply as repetitive AP?s that are both initiated and generated by a simple reciprocal activation of surface membrane ion currents that make up the Membrane Clock. The idea that a Ca2+ clock within pacemaker cells initiates and regulates normal pacemaking function provides the key that reunites pacemaker and ventricular cell research, thus permitting a General Theory of initiation and strength of the heartbeat. This common regulation of both cell types revolutionizes thought about novel therapies for heart failure, in which abnormalities of both rate and rhythm, and contractile strength routinely occur.