Catecholamine-Independent Heart Rate Increases Require Ca 2+ /Calmodulin-Dependent Protein Kinase II

Zhan Gao; Madhu V Singh; Duane D Hall; Olha M Koval; Elizabeth D Luczak; Mei-ling A Joiner; Biyi Chen; Yuejin Wu; Ashok K Chaudhary; James B Martins; Thomas J Hund; Peter J Mohler; Long-Sheng Song; Mark E Anderson

doi:10.1161/CIRCEP.110.961771

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Catecholamine-Independent Heart Rate Increases Require Ca 2+ /Calmodulin-Dependent Protein Kinase II

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Catecholamine-Independent Heart Rate Increases Require Ca 2+ /Calmodulin-Dependent Protein Kinase II

Zhan Gao, Madhu V Singh, Duane D Hall, Olha M Koval, Elizabeth D Luczak, Mei-ling A Joiner, Biyi Chen, Yuejin Wu, Ashok K Chaudhary, James B Martins, …

Circulation. Arrhythmia and electrophysiology, Vol.4(3), pp.379-387

06/2011

DOI: 10.1161/CIRCEP.110.961771

PMID: 21406683

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Abstract

Background: Catecholamines increase heart rate by augmenting the cAMP-responsive hyperpolarization-activated cyclic nucleotide-gated channel 4 pacemaker current (I(f)) and by promoting inward Na(+)/Ca(2+) exchanger current (I(NCX)) by a "Ca(2+) clock" mechanism in sinoatrial nodal cells (SANCs). The importance, identity, and function of signals that connect I(f) and Ca(2+) clock mechanisms are uncertain and controversial, but the multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is required for physiological heart rate responses to β-adrenergic receptor (β-AR) stimulation. The aim of this study was to measure the contribution of the Ca(2+) clock and CaMKII to cardiac pacing independent of β-AR agonist stimulation. Methods and results: We used the L-type Ca(2+) channel agonist Bay K8644 (BayK) to activate the SANC Ca(2+) clock. BayK and isoproterenol were similarly effective in increasing rates in SANCs and Langendorff-perfused hearts from wild-type control mice. In contrast, SANCs and isolated hearts from mice with CaMKII inhibition by transgenic expression of an inhibitory peptide (AC3-I) were resistant to rate increases by BayK. BayK only activated CaMKII in control SANCs but increased L-type Ca(2+) current (I(Ca)) equally in all SANCs, indicating that increasing I(Ca) was insufficient and suggesting that CaMKII activation was required for heart rate increases by BayK. BayK did not increase I(f) or protein kinase A-dependent phosphorylation of phospholamban (at Ser16), indicating that increased SANC Ca(2+) by BayK did not augment cAMP/protein kinase A signaling at these targets. Late-diastolic intracellular Ca(2+) release and I(NCX) were significantly reduced in AC3-I SANCs, and the response to BayK was eliminated by ryanodine in all groups. Conclusions: The Ca(2+) clock is capable of supporting physiological fight-or-flight responses, independent of β-AR stimulation or I(f) increases. Complete Ca(2+) clock and β-AR stimulation responses require CaMKII.

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Title: Subtitle: Catecholamine-Independent Heart Rate Increases Require Ca 2+ /Calmodulin-Dependent Protein Kinase II
Creators: Zhan Gao - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Madhu V Singh - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Duane D Hall - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Olha M Koval - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Elizabeth D Luczak - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Mei-ling A Joiner - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Biyi Chen - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Yuejin Wu - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Ashok K Chaudhary - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
James B Martins - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Thomas J Hund - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Peter J Mohler - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Long-Sheng Song - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Mark E Anderson - From the Departments of Internal Medicine (Z.G., M.V.S., D.D.H., O.M.K., E.D.L., M.A.J., B.C., Y.W., A.K.C., J.B.M., T.J.H., P.J.M., L.-S.S., M.E.A.) and Molecular Physiology and Biophysics (P.J.M., M.E.A.), Carver College of Medicine, University of Iowa, Iowa City, IA
Resource Type: Journal article
Publication Details: Circulation. Arrhythmia and electrophysiology, Vol.4(3), pp.379-387
DOI: 10.1161/CIRCEP.110.961771
PMID: 21406683
NLM abbreviation: Circ Arrhythm Electrophysiol
ISSN: 1941-3149
eISSN: 1941-3084
Language: English
Date published: 06/2011
Academic Unit: Cardiovascular Medicine; Biology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094573302771

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