Editors' ChoicePhysiology

The Fight or Flight of a Kinase

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Science Signaling  14 Apr 2009:
Vol. 2, Issue 66, pp. ec130
DOI: 10.1126/scisignal.266ec130

Heart rate increases during the “fight or flight” response, in part because β-adrenergic receptor stimulation activates the cyclic nucleotide-gated ion channel HCN4, which ultimately leads to quicker generation of action potentials in cardiac pacemaker cells in the sinoatrial node. However, HCN4-null mice still demonstrate increased heart rates when administered isoproterenol, a β-adrenergic receptor agonist, leading Wu et al. to investigate other mechanisms by which β-adrenergic receptors regulate heart rate. Mice with cardiomyocyte-specific expression of the autocamtide-3–derived peptide inhibitor (AC3-I) of calcium- and calmodulin-dependent protein kinase II (CaMKII) had lower stress-induced heart rates compared with wild-type mice or mice that expressed the scrambled AC3-I peptide (AC3-C). In addition, sinoatrial nodal cells from AC3-I mice exhibited reduced action potential frequencies in response to isoproterenol compared with cells from wild-type or AC3-C mice. CaMKII was activated (as measured by Thr287 phosphorylation immunofluorescence) by isoprotenerol treatment in sinoatrial nodal cells from wild-type or AC3-C mice but not AC3-I mice. Reasoning that Ca2+ release from the sarcoplasmic reticulum (SR) could increase action potential generation in sinoatrial nodal cells through a mechanism independent of HCN4, the authors showed that the SR in cells from AC3-I mice contained less Ca2+ than the SR in cells from wild-type or AC3-C mice, leading to decreased Ca2+ release from the SR (as measured by diastolic Ca2+ spark frequency) and diastolic depolarization rate (which determines heart rate) in response to isoproterenol. Thus, β-adrenergic receptor stimulation of the sinoatrial node appears to increase heart rate through multiple mechanisms.

Y. Wu, Z. Gao, B. Chen, O. M. Koval, M. V. Singh, X. Guan, T. J. Hund, W. Kutschke, S. Sarma, I. M. Grumbach, X. H. T. Wehrens, P. J. Mohler, L.-S. Song, M. E. Anderson, Calmodulin kinase II is required for fight or flight sinoatrial node physiology. Proc. Natl. Acad. Sci. U.S.A. 106, 5972–5977 (2009). [Abstract] [Full Text]

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