Progress in the Intracellular Clock that Drives the Hear

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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.