Calmodulin kinase II activity is required for normal atrioventricular nodal conduction.
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.


OBJECTIVE
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.
Khoo
Michelle S C
MS
Department of Internal Medicine, Vanderbilt University Medical School, Nashville, Tennessee 37232-6300, USA.
Kannankeril
Prince J
PJ
Li
Jingdong
J
Zhang
Rong
R
Kupershmidt
Sabina
S
Zhang
Wei
W
Atkinson
James B
JB
Colbran
Roger J
RJ
Roden
Dan M
DM
Anderson
Mark E
ME
D000704:Analysis of Variance; D000818:Animals; D001283:Atrioventricular Node / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction
D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases