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Rhythmic Ca 2+ Oscillations Drive Sinoatrial Nodal Cell Pacemaker Function to Make the Heart Tick
Author(s) -
VINOGRADOVA TATIANA M.,
MALTSEV VICTOR A.,
BOGDANOV KONSTANTIN Y.,
LYASHKOV ALEXEY E.,
LAKATTA EDWARD G.
Publication year - 2005
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.1341.013
Subject(s) - ryanodine receptor , chemistry , biophysics , depolarization , pacemaker potential , diastolic depolarization , endoplasmic reticulum , sinoatrial node , afterdepolarization , medicine , calcium , stimulation , myocyte , phospholamban , calsequestrin , endocrinology , repolarization , biology , electrophysiology , heart rate , biochemistry , organic chemistry , blood pressure
A bstract : Excitation‐induced Ca 2+ cycling into and out of the cytosol via the sarcoplasmic reticulum (SR) Ca 2+ pump, ryanodine receptor (RyR) and Na + ‐Ca 2+ exchanger (NCX) proteins, and modulation of this Ca 2+ cycling by β‐adrenergic receptor (β‐AR) stimulation, governs the strength of ventricular myocyte contraction and the cardiac contractile reserve. Recent evidence indicates that heart rate modulation and chronotropic reserve via β‐ARs also involve intracellular Ca 2+ cycling by these very same molecules. Specifically, sinoatrial nodal pacemaker cells (SANC), even in the absence of surface membrane depolarization, generate localized rhythmic, submembrane Ca 2+ oscillations via SR Ca 2+ pumping‐RyR Ca 2+ release. During spontaneous SANC beating, these rhythmic, spontaneous Ca 2+ oscillations are interrupted by the occurrence of an action potential (AP), which activates L‐type Ca 2+ channels to trigger SR Ca 2+ release, unloading the SR Ca 2+ content and inactivating RyRs. During the later part of the subsequent diastolic depolarization (DD), when Ca 2+ pumped back into the SR sufficiently replenishes the SR Ca 2+ content, and Ca 2+ ‐dependent RyR inactivation wanes, the spontaneous release of Ca 2+ via RyRs again begins to occur. The local increase in submembrane [Ca 2+ ] generates an inward current via NCX, enhancing the DD slope, modulating the occurrence of the next AP, and thus the beating rate. β‐AR stimulation increases the submembrane Ca 2+ oscillation amplitude and reduces the period (the time from the prior AP triggered SR Ca 2+ release to the onset of the local Ca 2+ release during the subsequent DD). This increased amplitude and phase shift causes the NCX current to occur at earlier times following a prior beat, promoting the earlier arrival of the next beat and thus an increase in the spontaneous firing rate. Ca 2+ cycling via the SR Ca 2+ pump, RyR and NCX, and its modulation by β‐AR stimulation is, therefore, a general mechanism of cardiac chronotropy and inotropy.