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The Missing Link in the Mystery of Normal Automaticity of Cardiac Pacemaker Cells
Author(s) -
Lakatta Edward G.,
Vinogradova Tatiana M.,
Maltsev Victor A.
Publication year - 2008
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1420.006
Subject(s) - ryanodine receptor , afterdepolarization , biophysics , chemistry , sinoatrial node , diastolic depolarization , pacemaker potential , membrane potential , endoplasmic reticulum , medicine , microbiology and biotechnology , endocrinology , biology , electrophysiology , repolarization , biochemistry , heart rate , blood pressure
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 (I K , I f ) 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 Ca 2+ clock (i.e., sarcoplasmic reticulum [SR] cycling Ca 2+ ). Sinoatrial cells, regardless of size, exhibit intense ryanodine receptor (RyR), Na + /Ca 2+ exchange (NCX)‐1, and SR Ca 2+ ATPase‐2 immunolabeling and dense submembrane NCX/RyR colocalization; Ca 2+ clocks generate spontaneous stochastic but roughly periodic local subsarcolemmal Ca 2+ releases (LCR). LCRs generate inward currents via NCX that exponentially accelerate the late DD. The timing and amplitude of LCR/I NCX ‐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 I CaL activation that initiates the next AP. LCR period is precisely controlled by the kinetics of SR Ca 2+ cycling, which, in turn, are regulated by 1) the status of protein kinase A‐dependent phosphorylation of SR Ca 2+ cycling proteins; and 2) membrane ion channels ensuring the Ca 2+ homeostasis and therefore the Ca 2+ available to Ca 2+ clock. Thus, the link between early DD and next AP, missed in earlier studies, is ensured by a precisely physiologically regulated Ca 2+ clock within pacemaker cells that integrates multiple Ca 2+ ‐dependent functions and rhythmically ignites APs during late DD via LCRs‐I NCX coupling.