The emergence of a general theory of the initiation and strength of the heartbeat

Victor A. Maltsev, Tatiana M. Vinogradovad, Edward G. Lakatta

Research output: Contribution to journalReview articlepeer-review

96 Scopus citations


Sarcoplasmic reticulum (SR) Ca2+ 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 Ca2+ and membrane clocks. In pacemaker cells the intracellular Ca2+ clock is manifested by spontaneous, rhythmic submembrane local Ca2+ releases from SR, which are tightly controlled by a high degree of basal and reserve PKA-dependent protein phosphorylation. The Ca2+ releases rhythmically activate Na+/Ca2+ 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 Ca2+ clock. The idea that spontaneous SR Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)338-369
Number of pages32
JournalJournal of Pharmacological Sciences
Issue number5
StatePublished - 2006
Externally publishedYes


  • Calcium cycling
  • Cardiac excitation
  • Contractility
  • Heart rate regulation
  • Pacemaker mechanism

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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