A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling

Jie Liu, Syevda Sirenko, Magdalena Juhaszova, Bruce Ziman, Veena Shetty, Silvia Rain, Shweta Shukla, Harold A. Spurgeon, Tatiana M. Vinogradova, Victor A. Maltsev, Edward G. Lakatta

Research output: Contribution to journalArticle

Abstract

Recent perspectives on sinoatrial nodal cell (SANC) * function indicate that spontaneous sarcoplasmic reticulum (SR) Ca 2+ cycling, i.e. an intracellular "Ca 2+ clock," driven by cAMP-mediated, PKA-dependent phosphorylation, interacts with an ensemble of surface membrane electrogenic molecules ("surface membrane clock") to drive SANC normal automaticity. The role of AC-cAMP-PKA-Ca 2+ signaling cascade in mouse, the species most often utilized for genetic manipulations, however, has not been systematically tested. Here we show that Ca 2+ cycling proteins (e.g. RyR2, NCX1, and SERCA2) are abundantly expressed in mouse SAN and that spontaneous, rhythmic SR generated local Ca 2+ releases (LCRs) occur in skinned mouse SANC, clamped at constant physiologic [Ca 2+]. Mouse SANC also exhibits a high basal level of phospholamban (PLB) phosphorylation at the PKA-dependent site, Serine16. Inhibition of intrinsic PKA activity or inhibition of PDE in SANC, respectively: reduces or increases PLB phosphorylation, and markedly prolongs or reduces the LCR period; and markedly reduces or accelerates SAN spontaneous firing rate. Additionally, the increase in AP firing rate by PKA-dependent phosphorylation by β-adrenergic receptor (β-AR) stimulation requires normal intracellular Ca 2+ cycling, because the β-AR chronotropic effect is markedly blunted when SR Ca 2+ cycling is disrupted. Thus, AC-cAMP-PKA-Ca 2+ signaling cascade is a major mechanism of normal automaticity in mouse SANC.

Original languageEnglish (US)
Pages (from-to)730-739
Number of pages10
JournalJournal of Molecular and Cellular Cardiology
Volume51
Issue number5
DOIs
StatePublished - Nov 1 2011
Externally publishedYes

Keywords

  • Adenylyl cyclase-cyclic amp-protein kinase a-Ca Signaling Cascade
  • Automaticity
  • Ca cycling proteins
  • Local Ca releases
  • Phospholamban phosphorylation
  • Sinoatrial node

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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    Liu, J., Sirenko, S., Juhaszova, M., Ziman, B., Shetty, V., Rain, S., Shukla, S., Spurgeon, H. A., Vinogradova, T. M., Maltsev, V. A., & Lakatta, E. G. (2011). A full range of mouse sinoatrial node AP firing rates requires protein kinase A-dependent calcium signaling. Journal of Molecular and Cellular Cardiology, 51(5), 730-739. https://doi.org/10.1016/j.yjmcc.2011.07.028