Sarcoplasmic reticulum Ca2+ pumping kinetics regulates timing of local Ca2+releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells

Tatiana M. Vinogradova, Didier X.P. Brochet, Syevda Sirenko, Yue Li, Harold Spurgeon, Edward G. Lakatta

Research output: Contribution to journalArticle

Abstract

Rationale: Sinoatrial node cells (SANCs) generate local, subsarcolemmal Ca2+ releases (LCRs) from sarcoplasmic reticulum (SR) during late diastolic depolarization. LCRs activate an inward Na+-Ca2+ exchange current (INCX), which accelerates diastolic depolarization rate, prompting the next action potential (AP). The LCR period, ie, a delay between AP-induced Ca2+ transient and LCR appearance, defines the time of late diastolic depolarization INCX activation. Mechanisms that control the LCR period, however, are still unidentified. Objective: To determine dependence of the LCR period on SR Ca2+ refilling kinetics and establish links between regulation of SR Ca2+ replenishment, LCR period, and spontaneous cycle length. Methods and Results: Spontaneous APs and SR luminal or cytosolic Ca2+ were recorded using perforated patch and confocal microscopy, respectively. Time to 90% replenishment of SR Ca2+ following AP-induced Ca2+ transient was highly correlated with the time to 90% decay of cytosolic Ca2+ transient (T-90C). Local SR Ca2+ depletions mirror their cytosolic counterparts, LCRs, and occur following SR Ca2+ refilling. Inhibition of SR Ca2+ pump by cyclopiazonic acid dose-dependently suppressed spontaneous SANCs firing up to ≈50%. Cyclopiazonic acid and graded changes in phospholamban phosphorylation produced by β-adrenergic receptor stimulation, phosphodiesterase or protein kinase A inhibition shifted T-90C and proportionally shifted the LCR period and spontaneous cycle length (R2=0.98). Conclusions: The LCR period, a critical determinant of the spontaneous SANC cycle length, is defined by the rate of SR Ca2+ replenishment, which is critically dependent on SR pumping rate, Ca2+ available for pumping, supplied by L-type Ca2+ channel, and ryanodine receptor Ca2+ release flux, each of which is modulated by cAMP-mediated protein kinase A-dependent phosphorylation.

Original languageEnglish (US)
Pages (from-to)767-775
Number of pages9
JournalCirculation research
Volume107
Issue number6
DOIs
StatePublished - Sep 17 2010
Externally publishedYes

Keywords

  • sarcoplasmic reticulum Ca pumping
  • sinoatrial nodal pacemaker cells
  • β-adrenergic receptor signaling

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Sarcoplasmic reticulum Ca<sup>2+</sup> pumping kinetics regulates timing of local Ca<sup>2+</sup>releases and spontaneous beating rate of rabbit sinoatrial node pacemaker cells'. Together they form a unique fingerprint.

  • Cite this