At similar physiological intracellular Ca2+ concentrations, local Ca2+ releases were large and rhythmic in permeabilized SANC but were small and random in permeabilized VM. Furthermore, SANC spontaneously released more Ca2+ from the sarcoplasmic reticulum than did VM, despite comparable sarcoplasmic reticulum Ca2+ content in both cell types. This ability of SANC to generate more robust and rhythmic local Ca2+ releases was associated with increased abundance of sarcoplasmic reticulum Ca2+-ATPase (SERCA), reduced abundance of the SERCA inhibitor phospholamban, and increased Ca2+-regulated PKA- and CaMKII-dependent phosphorylation of phospholamban and RyR. The increased phosphorylation of RyR in SANC may facilitate Ca2+ release from the sarcoplasmic reticulum, whereas Ca2+-dependent increase in phosphorylation of phospholamban relieves its inhibition of SERCA, augmenting the pumping rate of Ca2+ required to support robust, rhythmic local Ca2+ releases. The differences in Ca2+ cycling between SANC and VM provide insights into the regulation of clock-like intracellular Ca2+-cycling that drives normal automaticity of cardiac pacemaker cells. These insights may help in the design of gene- or cell-based biological pacemakers that could be used instead of electronic devices in individuals with sick sinus syndrome, which is primarily a disease of older persons and increases in an exponential manner with aging.

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