Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II

William H THIEL; BIYI CHEN; Thomas J HUND; Olha M KOVAL; Anil PUROHIT; Long-Sheng SONG; Peter J MOHLER; Mark E ANDERSON

doi:10.1161/CIRCULATIONAHA.108.788067

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Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II

Journal article

Open access

Peer reviewed

Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II

William H THIEL, BIYI CHEN, Thomas J HUND, Olha M KOVAL, Anil PUROHIT, Long-Sheng SONG, Peter J MOHLER and Mark E ANDERSON

Circulation (New York, N.Y.), Vol.118(22), pp.2225-2234

2008

DOI: 10.1161/CIRCULATIONAHA.108.788067

PMCID: PMC3226825

PMID: 19001023

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Abstract

Background: Timothy syndrome (TS) is a disease of excessive cellular Ca(2+) entry and life-threatening arrhythmias caused by a mutation in the primary cardiac L-type Ca(2+) channel (Ca(V)1.2). The TS mutation causes loss of normal voltage-dependent inactivation of Ca(V)1.2 current (I(Ca)). During cellular Ca(2+) overload, the calmodulin-dependent protein kinase II (CaMKII) causes arrhythmias. We hypothesized that CaMKII is a part of the proarrhythmic mechanism in TS. Methods and results: We developed an adult rat ventricular myocyte model of TS (G406R) by lentivirus-mediated transfer of wild-type and TS Ca(V)1.2. The exogenous Ca(V)1.2 contained a mutation (T1066Y) conferring dihydropyridine resistance, so we could silence endogenous Ca(V)1.2 with nifedipine and maintain peak I(Ca) at control levels in infected cells. TS Ca(V)1.2-infected ventricular myocytes exhibited the signature voltage-dependent inactivation loss under Ca(2+) buffering conditions, not permissive for CaMKII activation. In physiological Ca(2+) solutions, TS Ca(V)1.2-expressing ventricular myocytes exhibited increased CaMKII activity and a proarrhythmic phenotype that included action potential prolongation, increased I(Ca) facilitation, and afterdepolarizations. Intracellular dialysis of a CaMKII inhibitory peptide, but not a control peptide, reversed increases in I(Ca) facilitation, normalized the action potential, and prevented afterdepolarizations. We developed a revised mathematical model that accounts for CaMKII-dependent and CaMKII-independent effects of the TS mutation. Conclusions: In TS, the loss of voltage-dependent inactivation is an upstream initiating event for arrhythmia phenotypes that are ultimately dependent on CaMKII activation.

Cardiology. Vascular system

Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous

Biological and medical sciences

Injuries of the limb. Injuries of the spine

Medical sciences

Traumas. Diseases due to physical agents

Blood and lymphatic vessels

Details

Title: Subtitle: Proarrhythmic Defects in Timothy Syndrome Require Calmodulin Kinase II
Creators: William H THIEL - Vanderbilt University, Nashville, Tenn, United States
BIYI CHEN - University of Iowa, Iowa City, United States
Thomas J HUND - University of Iowa, Iowa City, United States
Olha M KOVAL - University of Iowa, Iowa City, United States
Anil PUROHIT - University of Iowa, Iowa City, United States
Long-Sheng SONG - University of Iowa, Iowa City, United States
Peter J MOHLER - University of Iowa, Iowa City, United States
Mark E ANDERSON - University of Iowa, Iowa City, United States
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.118(22), pp.2225-2234
DOI: 10.1161/CIRCULATIONAHA.108.788067
PMID: 19001023
PMCID: PMC3226825
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Language: English
Date published: 2008
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094368002771

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