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lüll Normal heart rhythm is initiated and regulated by an intracellular calcium clock within pacemaker cells Maltsev VA; Lakatta EGHeart Lung Circ 2007[Oct]; 16 (5): 335-48For almost half a century it has been thought that the heart rhythm originates on the surface membrane of the cardiac pacemaker cells and is driven by voltage-gated ion channels (membrane clocks). Data from several recent studies, however, conclusively show that the rhythm is initiated, sustained, and regulated by oscillatory Ca(2+) releases (Ca(2+) clock) from the sarcoplasmic reticulum, a major Ca(2+) store within sinoatrial node cells, the primary heart's pacemakers. Activation of the local oscillatory Ca(2+) releases is independent of membrane depolarisation and driven by a high level of basal state phosphorylation of Ca(2+) cycling proteins. The releases produce Ca(2+) wavelets under the cell surface membrane during the later phase of diastolic depolarisation and activate the forward mode of Na(+)/Ca(2+) exchanger resulting in inward membrane current, which ignites an action potential. Phosphorylation-dependent gradation of speed at which Ca(2+) clock cycles is the essential regulatory mechanism of normal pacemaker rate and rhythm. The robust regulation of pacemaker function is insured by tight integration of Ca(2+) and membrane clocks: the action potential shape and ion fluxes are tuned by membrane clocks to sustain operation of the Ca(2+) clock which produces timely and powerful ignition of the membrane clocks to effect action potentials.|Animals[MESH]|Biological Clocks/*physiology[MESH]|Calcium/*physiology[MESH]|Humans[MESH]|Myocardial Contraction/physiology[MESH]|Ryanodine Receptor Calcium Release Channel/*physiology[MESH]|Sarcoplasmic Reticulum/*physiology[MESH]|Sinoatrial Node/*physiology[MESH] |