Abstract
At the beginning of this century, debates regarding “what are the main control mechanisms that ignite the action potential (AP) in heart pacemaker cells” dominated the electrophysiology field. The original theory which prevailed for over 50 years had advocated that the ensemble of surface membrane ion channels (i.e., “M-clock”) is sufficient to ignite rhythmic APs. However, more recent experimental evidence in a variety of mammals has shown that the sarcoplasmic reticulum (SR) acts as a “Ca2+-clock” rhythmically discharges diastolic local Ca2+ releases (LCRs) beneath the cell surface membrane. LCRs activate an inward current (likely that of the Na+/Ca2+ exchanger) that prompts the surface membrane “M-clock” to ignite an AP. Theoretical and experimental evidence has mounted to indicate that this clock “crosstalk” operates on a beat-to-beat basis and determines both the AP firing rate and rhythm. Our review is focused on the evolution of experimental definition and numerical modeling of the coupled-clock concept, on how mechanisms intrinsic to pacemaker cell determine both the heart rate and rhythm, and on future directions to develop further the coupled-clock pacemaker cell concept.
Highlights
Under normal conditions, specialized, self-excitable pacemaker cells within the sinoatrial node (SAN) initiate the spontaneous action potentials (AP) that are conducted to the ventricle to entrain the rate and rhythm of ventricular myocytes contractions
Theoretical and experimental evidence has mounted to indicate that this clock “crosstalk” operates on a beat-to-beat basis and determines both the AP firing rate and rhythm
Crosstalk exists between M and Ca2+-clock and the tightness of this crosstalk, informed by the local Ca2+ releases (LCRs) period, determines the rate and rhythm of spontaneous AP generation
Summary
Under normal conditions, specialized, self-excitable pacemaker cells within the sinoatrial node (SAN) initiate the spontaneous action potentials (AP) that are conducted to the ventricle to entrain the rate and rhythm of ventricular myocytes contractions. Majority of the original experiments supporting the coupled-clock concept were performed in rabbit pacemaker cells, recent experimental results from mouse genetic models have clarified the role of many coupled-clock components: NCX (Groenke et al, 2013; Herrmann et al, 2013), If(Ludwig et al, 1998; Stieber et al, 2004; Herrmann et al, 2007), T-type channels (Mesirca et al, 2014), G protein signaling (Yang et al, 2010; Wydeven et al, 2014), Cav1.3 (Christel et al, 2012), CaMKII activity (Zhang et al, 2005; Gao et al, 2011) and ankyrin-B function (Le Scouarnec et al, 2008). Note that the relevant of studies in mice to other species with much lower hear rate has to be proven
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