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

Tatiana Vinogradova,Syevda Tagirova (Sirenko),Edward Lakatta

doi:10.3390/ijms19082173

Tatiana Vinogradova, Syevda Tagirova (Sirenko) + Show 1 more

Open Access

https://doi.org/10.3390/ijms19082173

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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.

Highlights

The heart beats over 3 billion times during a normal life-span
Intracellular sarcoplasmic reticulum (SR) Ca2+ cycling has distinct functions in pacemaker and cardiac muscle cells: in the former, it is involved in the generation of spontaneous action potentials, which are conducted to ventricular myocytes, and through excitation–contraction coupling initiate heartbeats
This has led to a general theory of cardiac chronotropy and inotropy [28]

Summary

Introduction

The sinoatrial (SA) node, the primary physiological pacemaker of the heart, is a specialized and relatively small area in the right atrium which spontaneously generates action potentials. Numerous reviews have described the contribution of ionic currents in the generation of the diastolic depolarization and cardiac pacemaker function [1,2,3,4]. Effects of changes in extracellular [Ca2+] on spontaneous beating rate of the intact SA node have been well established in early studies [5,6], but its effect on cardiac pacemaking was originally explained by Ca2+-induced changes in several ionic currents including If [7], ICa,T and ICa,L [8], IK [9,10], Ist [11], etc. The involvement of intracellular Ca2+ cycling in cardiac pacemaker function was studied over the decade [12,13,14,15,16,17,18], specific mechanisms of intracellular sarcoplasmic reticulum (SR)

Objectives

Conclusion