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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000260-06
Application #
8736509
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$292,840
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Vinogradova, Tatiana M; Tagirova Sirenko, Syevda; Lakatta, Edward G (2018) Unique Ca2+-Cycling Protein Abundance and Regulation Sustains Local Ca2+ Releases and Spontaneous Firing of Rabbit Sinoatrial Node Cells. Int J Mol Sci 19:
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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
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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
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
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

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