Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8)

Benjamin M L Drum, Rose Ellen Dickson, Can Yuan, Edward P. Cheng, Luis Fernando Santana

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Ca2+ flux through l-type CaV1.2 channels shapes the waveform of the ventricular action potential (AP) and is essential for excitation-contraction (EC) coupling. Timothy syndrome (TS) is a disease caused by a gain-of-function mutation in the CaV1.2 channel (CaV1.2-TS) that decreases inactivation of the channel, which increases Ca2+ influx, prolongs APs, and causes lethal arrhythmias. Although many details of the CaV1.2-TS channels are known, the cellular mechanisms by which they induce arrhythmogenic changes in intracellular Ca2+ remain unclear. We found that expression of CaV1.2-TS channels increased sarcolemmal Ca2+ "leak" in resting TS ventricular myocytes. This resulted in higher diastolic [Ca2+]i in TS ventricular myocytes compared to WT. Accordingly, TS myocytes had higher sarcoplasmic reticulum (SR) Ca2+ load and Ca2+ spark activity, larger amplitude [Ca2+]i transients, and augmented frequency of Ca2+ waves. The large SR Ca2+ release in TS myocytes had a profound effect on the kinetics of CaV1.2 current in these cells, increasing the rate of inactivation to a high, persistent level. This limited the amount of influx during EC coupling in TS myocytes. The relationship between the level of expression of CaV1.2-TS channels and the probability of Ca2+ wave occurrence was non-linear, suggesting that even low levels of these channels were sufficient to induce maximal changes in [Ca2+]i. Depolarization of WT cardiomyocytes with a TS AP waveform increased, but did not equalize [Ca2+]i, compared to depolarization of TS myocytes with the same waveform. We propose that CaV1.2-TS channels increase [Ca2+] in the cytosol and the SR, creating a Ca2+overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca2+ release.

Original languageEnglish (US)
Pages (from-to)63-71
Number of pages9
JournalJournal of Molecular and Cellular Cardiology
Volume66
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Calcium wave
  • Excitation-contraction coupling
  • Timothy syndrome
  • Ventricular myocyte

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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