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

摘要

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.