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

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

Research output: Contribution to journalReview article

Abstract

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
Volume100
Issue number5
DOIs
StatePublished - 2006
Externally publishedYes

Fingerprint

Sarcoplasmic Reticulum
Action Potentials
Membranes
Research
Intracellular Membranes
Ion Channels
Muscle Cells
Phosphorylation
Ions
Proteins

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

The emergence of a general theory of the initiation and strength of the heartbeat. / Maltsev, Victor A.; Vinogradovad, Tatiana M.; Lakatta, Edward.

In: Journal of Pharmacological Sciences, Vol. 100, No. 5, 2006, p. 338-369.

Research output: Contribution to journalReview article

Maltsev, Victor A. ; Vinogradovad, Tatiana M. ; Lakatta, Edward. / The emergence of a general theory of the initiation and strength of the heartbeat. In: Journal of Pharmacological Sciences. 2006 ; Vol. 100, No. 5. pp. 338-369.
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