Editorial: Ca2+ Signaling and Heart Rhythm

Ca 2+ is a strategic intracellular second messenger regulating multifarious cardiac cellular processes. This Frontiers issue on Ca 2+ signaling and cardiac rhythm first focuses on the spontaneous membrane depolarization triggering action potential (AP) pacing by sino-atrial node (SAN) cells. These drive normal rhythmic atrial followed by ventricular depolarization initiating effective systolic contraction (Mangoni and Nargeot, 2008). Classic pharmacological and immunological localization studies had implicated sarcoplasmic reticular (SR)-mediated Ca 2+ storage and release (Rigg and Terrar, 1996) involving ryanodine receptor (RyR2)-Ca 2+ release channels (Rigg et al., 2000) as necessary components in an adrenergically-responsive, complex, Ca 2+-dependent, sino-atrial pacing process. AP firing (Vinogradova et al., 2002). SAN cells possessed high basal cAMP and phosphokinase A-dependent phosphorylation levels (Vinogradova et al., 2006) that could ensure RyR2-mediated Ca 2+ release activity (Yang et al., 2002) at the requisite frequencies (Vinogradova et al., 2002, 2006). The resulting [Ca 2+ ] (to >100 nM) increases produced the expected I NCX changes (Bogdanov et al., 2001) besides additionally activating strategic enzymes, particularly calcium/calmodulin-dependent protein kinase II (CaMKII). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels carrying I f likely also importantly contribute to this process: Hcn4-/-and Hcn4-R669Q/R669Q mouse embryos were bradycardic with 75–90% reduced I f before eventual lethality (Stieber et al., 2003; Chandra et al., 2006; Harzheim et al., 2008); tamoxiphen-inducible adult hearts showed ∼70% reduced I f and progressive ≤50% reductions in, nevertheless persistent, SAN pacing, compromising its responses to isoproterenol challenge (Sohal et al., 2001; Baruscotti et al., 2011). The present articles first complete necessary conditions for such a Ca 2+-mediated pacing system (Vinogradova et al. 2007) to exist. They explore recent evidence implicating I NCX , combined with delayed rectifier K + current deactivation, in the pacemaker depolarization triggering I Ca (Capel and Terrar). Furthermore, intracellular [Ca 2+ ] proved instrumental in determining pacing rates: 1,2-bis(o-aminophenoxy)ethane-N,N,N ′ ,N ′-tetraacetic acid (BAPTA) dose-dependently slowed, ultimately abolishing, AP firing in isolated guinea-pig SAN myocytes (Capel and Terrar). Involvement of I Ca in both SAN pacing and atrioventricular conduction was indicated in mice homozygously lacking L-type, Cav1.3, or T-type, Cav3.1, channels normally expressed in mouse, rabbit and human