title: Normal heart rhythm is initiated and regulated by an intracellular calcium clock within pacemaker cells.
abstract: 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 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.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, Intramural Research Program, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D002118:Calcium / Q000502:physiology*; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology*; D012519:Sarcoplasmic Reticulum / Q000502:physiology*; D012849:Sinoatrial Node / Q000502:physiology*