Both PKA and CaMKII phosphorylation drive pacemaker cell automaticity

National Institute On Aging

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Abstract

We have discovered that at similar intracellular free Ca2+ concentrations (Ca2+f) LCRs in permeabilized SANC are large and rhythmic, while Ca2+ releases (Ca2+ sparks) in VM are small and random. At physiological Ca2+f SANC spontaneously release more Ca2+ from the sarcoplasmic reticulum (SR) than do VM, despite a comparable SR Ca2+ content in both cell types. This ability of SANC to generate more robust and rhythmic LCRs than VM occurs in the context of: (1) increased expression of SR Ca2+-ATPase (SERCA) and a reduced expression of phospholamban (PLB) proteins; and (2) Ca2+-dependent increase in both PKA- and CaMKII-dependent phosphorylation of Ca2+ cycling proteins, PLB and RyR. The increased RyR phosphorylation in SANC may facilitate SR Ca2+ release, while Ca2+-modulated increase of PLB phosphorylation relieves SERCA inhibition to adjust SR Ca2+ pumping to support robust, rhythmic LCRs. The discovery of substantial differences in Ca2+ cycling between SANC and VM provides new insights into regulation of clock-like intracellular Ca2+-cycling that drives normal automaticity of SANC.