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PNAS 106 (14): 5972-5977

Copyright © 2009 by the National Academy of Sciences.

From the Cover


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

Yuejin Wua,1, Zhan Gaoa,2, Biyi Chena,2, Olha M. Kovala, Madhu V. Singha, Xiaoqun Guana, Thomas J. Hunda, William Kutschkea, Satyam Sarmab, Isabella M. Grumbacha, Xander H. T. Wehrensb, Peter J. Mohlera,c, Long-Sheng Songa, and Mark E. Andersona,c,1

Departments of aInternal Medicine and cMolecular Physiology and Biophysics, University of Iowa, 2256 CBRB, Iowa City, IA 52242; and bDepartments of Molecular Physiology and Biophysics, and Medicine (in Cardiology), Baylor College of Medicine, One Baylor Plaza BCM335, Houston, TX 77030

Edited by William Jonathan Lederer, University of Maryland Biotechnology Institute, Baltimore, MD, and accepted by the Editorial Board January 26, 2009

Received for publication July 2, 2008.

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 If-independent pathways are critical to SAN fight or flight responses. The multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is a downstream signal in the βAR pathway that activates Ca2+ 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 Ca2+ homeostasis are critical for βAR agonist responses in SAN. Here we show that CaMKII mediates ISO HR increases by targeting SAN cell Ca2+ homeostasis. CaMKII inhibition prevents ISO effects on SAN Ca2+ 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 Ca2+ 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.

Key Words: sarcoplasmic reticulum • cardiac pacemaker • calcium • isoproterenol • HCN4

Author contributions: Y.W., X.H.T.W., P.J.M., L.-S.S., and M.E.A. designed research; Y.W., Z.G., B.C., O.M.K., M.V.S., T.J.H., W.K., S.S., and P.J.M. performed research; X.G., T.J.H., and I.M.G. contributed new reagents/analytic tools; Y.W., Z.G., B.C., O.M.K., M.V.S., S.S., X.H.T.W., P.J.M., L.-S.S., and M.E.A. analyzed data; and M.E.A. wrote the paper.

2Z.G. and B.C. contributed equally to this work.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission. W.J.L. is a guest editor invited by the Editorial Board.

This article contains supporting information online at

1To whom correspondence may be addressed. E-mail: yuejin-wu{at} or mark-e-anderson{at}

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