Progress in the Intracellular Clock that Drives the Hear

LCS科学家的新研究表明，细胞内的？在SANC内，肌浆网产生节律性的细胞内自发钙释放，点燃表膜的兴奋(SCARIC)。通过对起搏细胞膜下Ca~(2+)和膜电位的同步共聚焦成像(并得到数值模拟的支持)的实验证据表明，这些细胞的起搏功能受到产生节律性惊吓的Ca~(2+)钟和响应SCARIE的表膜钟的紧密整合的影响和稳定，从而立即产生适当形状的AP？S。因此，严格控制的节律性惊恐不仅微调窦房结细胞AP的放电，而且是节律性心跳的正式(启动)原因。钙离子时钟通过有节奏地整合多种钙依赖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律性。 心脏内的细胞？S起搏器，即窦房结细胞(SANC)，正常？自动兴奋？产生自发动作电位(AP、S)。膜离子通道的集合(？膜时钟？)膜电位决定了起搏器的瞬时电位变化，显然是自发房颤的直接原因，但表面膜钟也是正常起搏功能的正式原因，即起搏功能的主要原因或启动原因的想法，在智力和实验相锁中已经成为控制起搏器研究领域的教条。已经将近50年了。因此，起搏细胞的整个正常占空比被简单地描绘为重复的AP？S，它既是由组成膜时钟的表面膜离子电流的简单相互激活启动和产生的。起搏器细胞内的钙钟启动和调节正常起搏功能的想法提供了重新结合起搏器和心室细胞研究的关键，从而允许对心跳的启动和强度的一般理论。这两种细胞类型的共同调节使治疗心力衰竭的新疗法的思想发生了革命性的变化，在这种疗法中，心率和节律以及收缩强度的异常经常发生。

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.