title: Rhythmic Ca2+ oscillations drive sinoatrial nodal cell pacemaker function to make the heart tick.
abstract: 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 beta-adrenergic receptor (beta-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 beta-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. Beta-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 beta-AR stimulation is, therefore, a general mechanism of cardiac chronotropy and inotropy.
authors.affiliation: Laboratory of Cardiovascular Science, Intramural Research Program, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Vinogradova
authors.forename: Victor A
authors.initials: VA
authors.lastname: Maltsev
authors.forename: Konstantin Y
authors.initials: KY
authors.lastname: Bogdanov
authors.forename: Alexey E
authors.initials: AE
authors.lastname: Lyashkov
authors.forename: Edward G
authors.initials: EG
authors.lastname: Lakatta
mesh_terms: D001683:Biological Clocks / Q000502:physiology*; D020013:Calcium Signaling / Q000502:physiology*; D004594:Electrophysiology; D006339:Heart Rate / Q000502:physiology*; D010507:Periodicity; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D012849:Sinoatrial Node / Q000166:cytology / Q000502:physiology*; D019831:Sodium-Calcium Exchanger / Q000502:physiology
chemical_list: D011943:Receptors, Adrenergic, beta; D019837:Ryanodine Receptor Calcium Release Channel; D019831:Sodium-Calcium Exchanger