Camkii-dependent phosphorylation regulates basal cardiac pacemaker function via modulation of local ca2+ releases

Yue Li, Syevda Sirenko, Daniel R. Riordon, Dongmei Yang, Harold Spurgeon, Edward Lakatta, Tatiana M. Vinogradova

Research output: Contribution to journalArticle

Abstract

Spontaneous beating of the heart pacemaker, the sinoatrial node, is generated by sinoatrial node cells (SANC) due to gradual change of the membrane potential called diastolic depolarization (DD). Spontaneous, submembrane local Ca2+ releases (LCR) from ryanodine receptors (RyR) occur during late DD and activate an inward Na+/ Ca2+exchange current to boost the DD rate and fire an action potential (AP). Here we studied the extent of basal Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and the role of basal CaMKIIdependent protein phosphorylation in generation of LCRs and regulation of normal automaticity of intact rabbit SANC. The basal level of activated (autophosphorylated) CaMKII in rabbit SANC surpassed that in ventricular myocytes (VM) by approximately twofold, and this was accompanied by high basal level of protein phosphorylation. Specifically, phosphorylation of phospholamban (PLB) at the CaMKII-dependent Thr17 site was approximately threefold greater in SANC compared with VM, and RyR phosphorylation at CaMKIIdependent Ser2815 site was ~10-fold greater in the SA node, compared with that in ventricle. CaMKII inhibition reduced phosphorylation of PLB and RyR, decreased LCR size, increased LCR periods (time from AP-induced Ca2+ transient to subsequent LCR), and suppressed spontaneous SANC firing. Graded changes in CaMKIIdependent phosphorylation (indexed by PLB phosphorylation at the Thr17site) produced by CaMKII inhibition, β-AR stimulation or phosphodiesterase inhibition were highly correlated with changes in SR Ca2+ replenishment times and LCR periods and concomitant changes in spontaneous SANC cycle lengths (R2 = 0.96). Thus high basal CaMKII activation modifies the phosphorylation state of Ca2+ cycling proteins PLB, RyR, L-type Ca2+ channels (and likely others), adjusting LCR period and characteristics, and ultimately regulates both normal and reserve cardiac pacemaker function.

Original languageEnglish (US)
Pages (from-to)H532-H544
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume311
Issue number3
DOIs
StatePublished - Sep 1 2016
Externally publishedYes

Keywords

  • CaMKII-dependent phosphorylation
  • Phospholamban
  • Ryanodine receptors
  • Sarcoplasmic reticulum Ca-ATPase
  • Sinoatrial node cells

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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