Cellular mechanisms of ventricular arrhythmias in a mouse model of Timothy syndrome (long QT syndrome 8).
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.
Department of Physiology & Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Benjamin M L
BM
Drum
Department of Physiology & Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Rose E
RE
Dixon
Department of Physiology & Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Can
C
Yuan
Department of Physiology & Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA.
Edward P
EP
Cheng
Department of Physiology & Biophysics, University of Washington School of Medicine, Seattle, WA 98195, USA. Electronic address: santana@uw.edu.
Luis F
LF
Santana
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001321:Autistic Disorder; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D056966:Excitation Contraction Coupling; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism* / Q000473:pathology; D008133:Long QT Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013576:Syndactyly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
C514350:CACNA1C protein, mouse; D020746:Calcium Channels, L-Type; D002118:Calcium
Ca(V)1.2; Calcium wave; Excitation–contraction coupling; Timothy syndrome; Ventricular myocyte