Normal Heart Rhythm is Initiated and Regulated by an Intracellular Calcium Clock Within Pacemaker Cells

For 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 Ca²⁺ releases (Ca²⁺ clock) from the sarcoplasmic reticulum, a major Ca²⁺ store within sinoatrial node cells, the primary heart's pacemakers. Activation of the local oscillatory Ca²⁺ releases is independent of membrane depolarisation and driven by a high level of basal state phosphorylation of Ca²⁺ cycling proteins. The releases produce Ca²⁺ wavelets under the cell surface membrane during the later phase of diastolic depolarisation and activate the forward mode of Na⁺/Ca²⁺ exchanger resulting in inward membrane current, which ignites an action potential. Phosphorylation-dependent gradation of speed at which Ca²⁺ 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 Ca²⁺ and membrane clocks: the action potential shape and ion fluxes are tuned by membrane clocks to sustain operation of the Ca²⁺ clock which produces timely and powerful ignition of the membrane clocks to effect action potentials.