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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
Application #
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Institute on Aging
Zip Code
Sirenko, Syevda G; Maltsev, Victor A; Yaniv, Yael et al. (2016) Electrochemical Na+ and Ca2+ gradients drive coupled-clock regulation of automaticity of isolated rabbit sinoatrial nodal pacemaker cells. Am J Physiol Heart Circ Physiol 311:H251-67
Li, Yue; Sirenko, Syevda; Riordon, Daniel R et al. (2016) CaMKII-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local Ca2+ releases. Am J Physiol Heart Circ Physiol 311:H532-44
Sirenko, Syevda; Maltsev, Victor A; Maltseva, Larissa A et al. (2014) Sarcoplasmic reticulum Ca2+ cycling protein phosphorylation in a physiologic Ca2+ milieu unleashes a high-power, rhythmic Ca2+ clock in ventricular myocytes: relevance to arrhythmias and bio-pacemaker design. J Mol Cell Cardiol 66:106-15
Sirenko, Syevda; Yang, Dongmei; Li, Yue et al. (2013) Ca²?-dependent phosphorylation of Ca²? cycling proteins generates robust rhythmic local Ca²? releases in cardiac pacemaker cells. Sci Signal 6:ra6
Lakatta, Edward G; Maltsev, Victor A (2012) Rebuttal: what I(f) the shoe doesn't fit? ""The funny current has a major pacemaking role in the sinus node"". Heart Rhythm 9:459-60
Zahanich, Ihor; Sirenko, Syevda G; Maltseva, Larissa A et al. (2011) Rhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling. J Mol Cell Cardiol 50:66-76
Vinogradova, Tatiana M; Brochet, Didier X P; Sirenko, Syevda et al. (2010) Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+ releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells. Circ Res 107:767-75
Lyashkov, Alexey E; Vinogradova, Tatiana M; Zahanich, Ihor et al. (2009) Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca(2+) cycling and I(KACh). Am J Physiol Heart Circ Physiol 297:H949-59
Vinogradova, Tatiana M; Lakatta, Edward G (2009) Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels. J Mol Cell Cardiol 47:456-74
Younes, Antoine; Lyashkov, Alexey E; Graham, David et al. (2008) Ca(2+) -stimulated basal adenylyl cyclase activity localization in membrane lipid microdomains of cardiac sinoatrial nodal pacemaker cells. J Biol Chem 283:14461-8