Excitation-induced Ca2+ cycling into and out of the cytosol via the sarcoplasmic reticulum (SR) Ca2+ pump, ryanodine receptor (RyR) and Na+-Ca2+ exchanger (NCX) proteins, and modulation of this Ca2+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 Ca2+ cycling by these very same molecules. Specifically, sinoatrial nodal pacemaker cells (SANC), even in the absence of surface membrane depolarization, generate localized rhythmic, submembrane Ca2+ oscillations via SR Ca2+ pumping-RyR Ca2+ release. During spontaneous SANC beating, these rhythmic, spontaneous Ca2+ oscillations are interrupted by the occurrence of an action potential (AP), which activates L-type Ca2+ channels to trigger SR Ca2+ release, unloading the SR Ca2+ 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 Ca2+-dependent RyR inactivation wanes, the spontaneous release of Ca2+via RyRs again begins to occur. The local increase in submembrane [Ca2+] 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 Ca2+ oscillation amplitude and reduces the period (the time from the prior AP triggered SR Ca2+ release to the onset of the local Ca2+ 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. Ca2+ cycling via the SR Ca2+ pump, RyR and NCX, and its modulation by β-AR stimulation is, therefore, a general mechanism of cardiac chronotropy and inotropy.
- Beta-adrenergic receptor stimulation
- Local Ca release
- Ryanodine receptor
- Sinoatrial nodal cells
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
- History and Philosophy of Science