Unique Ca2+-Cycling Protein Abundance and Regulation Sustains Local Ca2+ Releases and Spontaneous Firing of Rabbit Sinoatrial Node Cells

Abstract

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) and caused by gradual change of the membrane potential called diastolic depolarization (DD). Submembrane local Ca2+ releases (LCR) from sarcoplasmic reticulum (SR) occur during late DD and activate an inward Na+/Ca2+ exchange current, which accelerates the DD rate leading to earlier occurrence of an action potential. A comparison of intrinsic SR Ca2+ cycling revealed that, at similar physiological Ca2+ concentrations, LCRs are large and rhythmic in permeabilized SANC, but small and random in permeabilized ventricular myocytes (VM). Permeabilized SANC spontaneously released more Ca2+ from SR than VM, despite comparable SR Ca2+ content in both cell types. In this review we discuss specific patterns of expression and distribution of SR Ca2+ cycling proteins (SR Ca2+ ATPase (SERCA2), phospholamban (PLB) and ryanodine receptors (RyR)) in SANC and ventricular myocytes. We link ability of SANC to generate larger and rhythmic LCRs with increased abundance of SERCA2, reduced abundance of the SERCA inhibitor PLB. In addition, an increase in intracellular [Ca2+] increases phosphorylation of both PLB and RyR exclusively in SANC. The differences in SR Ca2+ cycling protein expression between SANC and VM provide insights into diverse regulation of intrinsic SR Ca2+ cycling that drives automaticity of SANC.

The Ionotropic P2X4 Receptor has Unique Properties in the Heart by Mediating the Negative Chronotropic Effect of ATP While Increasing the Ventricular Inotropy

“…The unstable resting membrane potential characteristic of SAN cardiomyocytes is mainly due to mutual influence of intracellular Ca 2+ “clocks” and membrane potential oscillations. The unstable resting membrane potential and the spontaneous firing of SAN cardiomyocytes are mainly attributed to “funny” currents carried by hyperpolarization-activated cyclic nucleotide-gated channels (HCN) and by the electrogenic Na + /Ca 2+ exchanger (NCX) functioning in the forward Ca 2+ -extrusion mode (Tsutsui et al, 2018; Vinogradova et al, 2018). NCX operates as an integrator of intracellular Ca 2+ with the membrane potential, in a way that it is responsible by a slow depolarizing current that drives the diastolic depolarization phase in response to calcium leakage from sarcoplasmatic reticulum and other subsidiary Ca 2+ stores (Bogdanov et al, 2001; Sanders et al, 2006; Groenke et al, 2013; Herrmann et al, 2013).…”

TRPV1 channels regulate the automaticity of embryonic stem cell‐derived cardiomyocytes through stimulating the Na+/Ca2+ exchanger current

“…However, even though the SR Ca 2+ contents are comparable in SANCs and ventricular cardiomyocytes, SANCs display more robust and periodic local Ca 2+ release than ventricular cardiomyocytes (Sirenko et al, 2013). Accordingly, the abundance of RyR and SERCA in SANCs exceeds those in ventricular cardiomyocytes (Vinogradova et al, 2018). We speculate that the presence of TRPV1 on the SR in mESC‐CMs (more SAN‐like) would necessitate the fine control of the robust and periodic Ca 2+ clock in SANCs.…”

Speeding Up the Heart? Traditional and New Perspectives on HCN4 Function

“…The extent of LCRs critically depends on SR Ca 2+ load, which in turn is regulated by the activity of the sarco-/endoplasmic reticulum Ca 2+ ATPase (SERCA) that refills the SR Ca 2+ stores after action potential termination ( Vinogradova et al, 2010 ). The Ca 2+ reuptake into the SR is significantly regulated by phospholamban, a 52-amino acid peptide directly inhibiting SERCA activity ( Vinogradova et al, 2018 ). This calcium clock concept was mainly derived from confocal calcium imaging experiments in isolated cells of the SAN.…”