title: The emergence of a general theory of the initiation and strength of the heartbeat.
abstract: Sarcoplasmic reticulum (SR) Ca(2+) cycling, that is, the Ca(2+) clock, entrained by externally delivered action potentials has been a major focus in ventricular myocyte research for the past 5 decades. In contrast, the focus of pacemaker cell research has largely been limited to membrane-delimited pacemaker mechanisms (membrane clock) driven by ion channels, as the immediate cause for excitation. Recent robust experimental evidence, based on confocal cell imaging, and supported by numerical modeling suggests a novel concept: the normal rhythmic heart beat is governed by the tight integration of both intracellular Ca(2+) and membrane clocks. In pacemaker cells the intracellular Ca(2+) clock is manifested by spontaneous, rhythmic submembrane local Ca(2+) releases from SR, which are tightly controlled by a high degree of basal and reserve PKA-dependent protein phosphorylation. The Ca(2+) releases rhythmically activate Na(+)/Ca(2+) exchange inward currents that ignite action potentials, whose shape and ion fluxes are tuned by the membrane clock which, in turn, sustains operation of the intracellular Ca(2+) clock. The idea that spontaneous SR Ca(2+) releases initiate and regulate normal automaticity provides the key that reunites pacemaker and ventricular cell research, thus evolving a general theory of the initiation and strength of the heartbeat.
authors.affiliation: Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Vinogradova
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D000200:Action Potentials; D000818:Animals; D001683:Biological Clocks / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D006339:Heart Rate / Q000502:physiology*; D006352:Heart Ventricles / Q000166:cytology; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000502:physiology
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger; D002118:Calcium