Calmodulin kinase II is required for fight or flight sinoatrial node physiology

Yuejin Wu, Zhan Gao, Biyi Chen, Olha M. Koval, Madhu V. Singh, Xiaoqun Guan, Thomas J. Hund, William Kutschke, Satyam Sarma, Isabella M. Grumbach, Xander H.T. Wehrens, Peter J. Mohler, Long Sheng Song, Mark E. Anderson

Research output: Contribution to journalArticle

93 Scopus citations

Abstract

The best understood ''fight or flight'' mechanism for increasing heart rate (HR) involves activation of a cyclic nucleotide-gated ion channel (HCN4) by β-adrenergic receptor (βAR) agonist stimulation. HCN4 conducts an inward ''pacemaker'' current (If) that increases the sinoatrial nodal (SAN) cell membrane diastolic depolarization rate (DDR), leading to faster SAN action potential generation. Surprisingly, HCN4 knockout mice were recently shown to retain physiological HR increases with isoproterenol (ISO), suggesting that other I f -independent pathways are critical to SAN fight or flight responses. The multifunctional Ca 2+ and calmodulindependent protein kinase II (CaMKII) is a downstream signal in the |3AR pathway that activates Ca 2+ homeostatic proteins in ventricular myocardium. Mice with genetic, myocardial and SAN cell CaMKII inhibition have significantly slower HRs than controls during stress, leading us to hypothesize that CaMKII actions on SAN Ca 2+ homeostasis are critical for βAR agonist responses in SAN. Here we show that CaMKII mediates ISO HR increases by targeting SAN cell Ca 2+ homeostasis. CaMKII inhibition prevents ISO effects on SAN Ca 2+ uptake and release from intracellular sarcoplasmic reticulum (SR) stores that are necessary for increasing DDR. CaMKII inhibition has no effect on the ISO response in SAN cells when SR Ca 2+ release is disabled and CaMKII inhibition is only effective at slowing HRs during βAR stimulation. These studies show the tightly coupled, but previously unanticipated, relationship of CaMKII to the βAR pathway in fight or flight physiology and establish CaMKII as a critical signaling molecule for physiological HR responses to catecholamines.

Original languageEnglish (US)
Pages (from-to)5972-5977
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number14
DOIs
StatePublished - Apr 7 2009

Keywords

  • Calcium
  • Cardiac pacemaker
  • HCN4
  • Isoproterenol
  • Sarcoplasmic reticulum

ASJC Scopus subject areas

  • General

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    Wu, Y., Gao, Z., Chen, B., Koval, O. M., Singh, M. V., Guan, X., Hund, T. J., Kutschke, W., Sarma, S., Grumbach, I. M., Wehrens, X. H. T., Mohler, P. J., Song, L. S., & Anderson, M. E. (2009). Calmodulin kinase II is required for fight or flight sinoatrial node physiology. Proceedings of the National Academy of Sciences of the United States of America, 106(14), 5972-5977. https://doi.org/10.1073/pnas.0806422106