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

Autor: Rose E. Dixon, Luis Fernando Santana, Benjamin M.L. Drum, C. Yuan, Edward P. Cheng
Rok vydání: 2014
Předmět:
Ventricular myocyte
Medical Physiology
Timothy syndrome
Gene Expression
Action Potentials
Cardiorespiratory Medicine and Haematology
Ca(V)1.2
Cardiovascular
Cav1.2
Mice
2.1 Biological and endogenous factors
Myocyte
Myocytes
Cardiac
Aetiology
Excitation Contraction Coupling
biology
Depolarization
L-Type
Sarcoplasmic Reticulum
Long QT Syndrome
Heart Disease
Cardiology and Cardiovascular Medicine
Cardiac
medicine.medical_specialty
Calcium Channels
L-Type
Heart Ventricles
Long QT syndrome
chemistry.chemical_element
Calcium
Calcium wave
Article
Ventricular action potential
Excitation–contraction coupling
Internal medicine
medicine
Animals
Autistic Disorder
Molecular Biology
Myocytes
Animal
Endoplasmic reticulum
medicine.disease
Excitation-contraction coupling
Disease Models
Animal
Endocrinology
Cardiovascular System & Hematology
chemistry
Disease Models
biology.protein
Syndactyly
Calcium Channels
Zdroj: Journal of Molecular and Cellular Cardiology. 66:63-71
ISSN: 0022-2828
DOI: 10.1016/j.yjmcc.2013.10.021
Popis: 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.
Databáze: OpenAIRE
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