The integration of spontaneous intracellular Ca2+ cycling and surface membrane ion channel activation entrains normal automaticity in cells of the heart's pacemaker

Edward G. Lakatta, Tatiana Vinogradova, Alexey Lyashkov, Syevda Sirenko, Weizong Zhu, Abdul Ruknudin, Victor A. Maltsev

Research output: Chapter in Book/Report/Conference proceedingConference contribution


Although the ensemble of voltage- and time-dependent rhythms of surface membrane ion channels, the membrane "Clock", is the immediate cause of a sinoatrial nodal cell (SANC) action potential (AP), it does not necessarily follow that this ion channel ensemble is the formal cause of spontaneous, rhythmic APs. SANC also generates intracellular oscillatory spontaneous Ca 2+ releases that ignite excitation (SCaRIE) of the surface membrane via Na+/Ca2+ exchanger activation. The idea that a rhythmic intracellular Ca2+ Clock might keep time for normal automaticity of SANC, however, has not been assimilated into mainstream pacemaker dogma. Recent experimental evidence, derived from simultaneous, confocal imaging of submembrane Ca2+ and membrane potential of SANC, and supported by numerical modeling, indicates that normal automaticity of SANC is entrained and stabilized by the tight integration of the SR Ca2+ Clock that generates rhythmic SCaRIE, and the surface membrane Clock that responds to SCaRIE to immediately produce APs of an adequate shape. Thus, tightly controlled, rhythmic SCaRIE does not merely fine tune SANC AP firing, but is the formal cause of the basal and reserve rhythms, insuring pacemaker stability by rhythmically integrating multiple Ca2+-dependent functions, and effects normal automaticity by rhythmic ignition of the surface membrane Clock.

Original languageEnglish (US)
Title of host publicationInteractive and Integrative Cardiology
PublisherBlackwell Publishing Inc.
Number of pages29
ISBN (Print)1573316512, 9781573316514
StatePublished - Oct 2006
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632


  • Cardiac pacemaker
  • Na /Ca exchanger
  • Normal automaticity
  • Ryanodine receptor
  • Sarcoplasmic reticulum
  • Spontaneous local Ca release

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • History and Philosophy of Science

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