Calmodulin kinase II activity is required for normal atrioventricular nodal conduction

Michelle S.C. Khoo, Prince J. Kannankeril, Jingdong Li, Rong Zhang, Sabina Kupershmidt, Wei Zhang, James B. Atkinson, Roger J. Colbran, Dan M. Roden, Mark E. Anderson

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is abundant in myocardium. CaMKII activity is augmented by catecholamine stimulation, which enhances AV nodal conduction, suggesting the hypothesis that CaMKII also contributes to AV nodal conduction properties. Objectives: The purpose of this study was to test the potential role of CaMKII in regulating AV nodal conduction in heart. Methods: We developed a novel mouse with genetic CaMKII inhibition by cardiac-specific expression of autocamtide 3 inhibitory peptide (AC3-I) mimicking a conserved sequence of the CaMKII regulatory domain. We also engineered a control transgenic mouse with cardiac expression of an inactive, scrambled version of AC3-I (autocamtide 3 control peptide [AC3-C]) and performed electrophysiologic measurements in vivo and in Langendorff-perfused isolated hearts. Results: AC3-I and AC3-C were abundantly expressed in AV nodal cells. AC3-I mice with implanted ECG telemeters showed enhanced Wenckebach-type AV conduction block after isoproterenol (present in 9/9 mice) compared with AC3-C mice (present in 1/5 mice, P = .005). Intracardiac recordings showed significant PR and AH interval prolongation in AC3-I mice at baseline and after isoproterenol compared with AC3-C mice. HV durations were not different. Langendorff-perfused AC3-I hearts had significantly prolonged Wenckebach cycle lengths and AV nodal effective refractory periods compared with AC3-C hearts, whereas sinus node recovery time and left ventricular effective refractory times were similar between these genotypes. Conclusions: These studies define CaMKII as a critical determinant of normal and catecholamine-stimulated AV nodal conduction responses.

Original languageEnglish (US)
Pages (from-to)634-640
Number of pages7
JournalHeart Rhythm
Volume2
Issue number6
DOIs
StatePublished - Jun 2005
Externally publishedYes

Keywords

  • Atrioventricular node
  • Calmodulin kinase II
  • Cellular signaling

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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