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

Abstract

Ca(2+) 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 Ca(2+) 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 Ca(2+) remain unclear. We found that expression of CaV1.2-TS channels increased sarcolemmal Ca(2+) "leak" in resting TS ventricular myocytes. This resulted in higher diastolic [Ca(2+)]i in TS ventricular myocytes compared to WT. Accordingly, TS myocytes had higher sarcoplasmic reticulum (SR) Ca(2+) load and Ca(2+) spark activity, larger amplitude [Ca(2+)]i transients, and augmented frequency of Ca(2+) waves. The large SR Ca(2+) 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 Ca(2+) wave occurrence was non-linear, suggesting that even low levels of these channels were sufficient to induce maximal changes in [Ca(2+)]i. Depolarization of WT cardiomyocytes with a TS AP waveform increased, but did not equalize [Ca(2+)]i, compared to depolarization of TS myocytes with the same waveform. We propose that CaV1.2-TS channels increase [Ca(2+)] in the cytosol and the SR, creating a Ca(2+)overloaded state that increases the probability of arrhythmogenic spontaneous SR Ca(2+) release.

• Authors: Benjamin M L Drum, Rose E Dixon, Can Yuan, Edward P Cheng, Luis F Santana
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 66 Pg. 63-71 (Jan 2014) ISSN: 1095-8584 [Electronic] England
• PMID: 24215710 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• CACNA1C protein, mouse
• Calcium Channels, L-Type
• Calcium

Topics

• Action Potentials (physiology)
• Animals
• Autistic Disorder
• Calcium (metabolism)
• Calcium Channels, L-Type (genetics, metabolism)
• Disease Models, Animal
• Excitation Contraction Coupling
• Gene Expression
• Heart Ventricles (metabolism, pathology)
• Long QT Syndrome (genetics, metabolism, pathology)
• Mice
• Myocytes, Cardiac (metabolism, pathology)
• Sarcoplasmic Reticulum (metabolism)
• Syndactyly (genetics, metabolism, pathology)