A Single Protein Kinase A or Calmodulin Kinase II Site Does Not Control the Cardiac Pacemaker Ca2+ Clock

Yuejin Wu, Héctor H. Valdivia, Xander H.T. Wehrens, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background-Fight or flight heart rate (HR) increases depend on protein kinase A (PKA)-and calmodulin kinase II (CaMKII)-mediated enhancement of Ca2+ uptake and release from sarcoplasmic reticulum (SR) in sinoatrial nodal cells (SANC). However, the impact of specific PKA and CaMKII phosphorylation sites on HR is unknown. Methods and Results-We systematically evaluated validated PKA and CaMKII target sites on phospholamban and the ryanodine receptor using genetically modified mice. We found that knockin alanine replacement of ryanodine receptor PKA (S2808) or CaMKII (S2814) target sites failed to affect HR responses to isoproterenol or spontaneous activity in vivo or in SANC. Similarly, selective mutation of phospholamban amino acids critical for enhancing SR Ca2+ uptake by PKA (S16) or CaMKII (T17) to alanines did not affect HR in vivo or in SANC. In contrast, CaMKII inhibition by expression of AC3-I has been shown to slow SANC rate responses to isoproterenol and decrease SR Ca2+ content. Phospholamban deficiency rescued SR Ca2+ content and SANC rate responses to isoproterenol in mice with AC3-I expression, suggesting that CaMKII affects HR by modulation of SR Ca2+ content. Consistent with this, mice expressing a superinhibitory phospholamban mutant had low SR Ca2+ content and slow HR in vivo and in SANC. Conclusions-SR Ca2+ depletion reduces HR and SR Ca2+ repletion restores physiological SANC rate responses, despite CaMKII inhibition. PKA and CaMKII do not affect HR by a unique target site governing SR Ca2+ uptake or release. HR acceleration may require an SR Ca2+ content threshold.

Original languageEnglish (US)
Article numbere003180
JournalCirculation: Arrhythmia and Electrophysiology
Issue number2
StatePublished - Feb 1 2016


  • calcium/calmodulin-dependent protein kinase II
  • heart rate
  • phospholamban
  • protein kinase A
  • ryanodine receptor
  • sinoatrial node

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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