The missing link in the mystery of normal automaticity of cardiac pacemaker cells

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

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

Abstract

Earlier studies of the initiating event of normal automaticity of the heart's pacemaker cells, inspired by classical quantitative membrane theory, focused upon ion currents (IK, If) that determine the maximum diastolic potential and the early phase of the spontaneous diastolic depolarization (DD). These early DD events are caused by the prior action potential (AP) and essentially reflect a membrane recovery process. Events following the recovery process that ignite APs have not been recognized and remained a mystery until recently. These critical events are linked to rhythmic intracellular signals initiated by Ca2+ clock (i.e., sarcoplasmic reticulum [SR] cycling Ca2+). Sinoatrial cells, regardless of size, exhibit intense ryanodine receptor (RyR), Na+/Ca2+ exchange (NCX)-1, and SR Ca2+ ATPase-2 immunolabeling and dense submembrane NCX/RyR colocalization; Ca2+ clocks generate spontaneous stochastic but roughly periodic local subsarcolemmal Ca2+ releases (LCR). LCRs generate inward currents via NCX that exponentially accelerate the late DD. The timing and amplitude of LCR/INCX-coupled events control the timing and amplitude of the nonlinear terminal DD and therefore ultimately control the chronotropic state by determining the timing of the ICaL activation that initiates the next AP. LCR period is precisely controlled by the kinetics of SR Ca2+ cycling, which, in turn, are regulated by 1) the status of protein kinase A-dependent phosphorylation of SR Ca2+ cycling proteins; and 2) membrane ion channels ensuring the Ca2+ homeostasis and therefore the Ca2+ available to Ca2+ clock. Thus, the link between early DD and next AP, missed in earlier studies, is ensured by a precisely physiologically regulated Ca2+ clock within pacemaker cells that integrates multiple Ca2+-dependent functions and rhythmically ignites APs during late DD via LCRs-INCX coupling.

Original languageEnglish (US)
Title of host publicationControl and Regulation of Transport Phenomena in the Cardiac System
PublisherBlackwell Publishing Inc.
Pages41-57
Number of pages17
ISBN (Print)9781573317061
DOIs
StatePublished - Mar 2008
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1123
ISSN (Print)0077-8923
ISSN (Electronic)1749-6632

Keywords

  • Calcium
  • Cardiac pacemaker
  • Na-Ca exchanger
  • Ryanodine receptor
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'The missing link in the mystery of normal automaticity of cardiac pacemaker cells'. Together they form a unique fingerprint.

Cite this