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

Research output: Contribution to journalArticlepeer-review


Background - Timothy syndrome (TS) is a disease of excessive cellular Ca2+ entry and life-threatening arrhythmias caused by a mutation in the primary cardiac L-type Ca2+ channel (CaV1.2). The TS mutation causes loss of normal voltage-dependent inactivation of Ca V1.2 current (ICa). During cellular Ca2+ 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 Cav1.2. The exogenous CaV1.2 contained a mutation (T1066Y) conferring dihydropyridine resistance, so we could silence endogenous Ca V1.2 with nifedipine and maintain peak ICa at control levels in infected cells. TS CaV1.2-infected ventricular myocytes exhibited the signature voltage-dependent inactivation loss under Ca 2+ buffering conditions, not permissive for CaMKII activation. In physiological Ca2+ solutions, TS CaV1.2-expressing ventricular myocytes exhibited increased CaMKII activity and a proarrhythmic phenotype that included action potential prolongation, increased ICa, 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. Conclusion - In TS, the loss of voltage-dependent inactivation is an upstream initiating event for arrhythmia phenotypes that are ultimately dependent on CaMKII activation.

Original languageEnglish (US)
Pages (from-to)2225-2234
Number of pages10
Issue number22
StatePublished - Nov 25 2008
Externally publishedYes


  • Action potentials
  • Calcium
  • Ion channels
  • Long-QT syndrome myocytes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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