期刊
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
卷 49, 期 1, 页码 95-105出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2010.03.006
关键词
Arrhythmias; Sarcoplasmic reticulum; Calsequestrin; Mutation; Ca2+ handling
资金
- DFG [Ki653/13-1, 13/2, Schu1082/3-1, 3-2]
- Leducq Foundation [CVD05]
Mutations in the human cardiac calsequestrin gene (CASQ2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT-2). This inherited disorder is characterized by life-threatening arrhythmias induced by physical and emotional stress in young patients Here we identified a novel heterozygous missense mutation (K206N) in the CASQ2 gene in a symptomatic family in which one member died of cardiac arrest. The functional properties of CSQ(K206N) were investigated in comparison to the wild-type form of CASQ2 (CSQ(WT)) by expression in eukaryotic cell lines and neonatal mouse myocytes The mutation created an additional N-glycosylation site resulting in a higher molecular weight form of the recombinant protein on immunoblots The mutation reduced the Ca2+ binding capacity of the protein and exhibited an altered aggregation state Consistently, CSQ(K206N)-expressing myocytes exhibited an impaired response to caffeine administration, suggesting a lower Ca2+ load of the sarcoplasmic reticulum (SR) The interaction of the mutated CSQ with triadin and the protein levels of the ryanodine receptor were unchanged but the maximal specific [H-3]ryanodine binding was increased in CSQ(K206N)-expressing myocytes, suggesting a higher opening state of the SR Ca2+ release channel Myocytes with expression of CSQ(K206N) showed a higher rate of spontaneous SR Ca2+ releases under basal conditions and after beta-adrenergic stimulation. We conclude that CSQ(K206N) caused a reduced Ca2+ binding leading to an abnormal regulation of intracellular Ca2+ in myocytes. This may then contribute to the increased propensity to trigger spontaneous Ca2+ transients in CSQ(K206N)-expressing myocytes (C) 2010 Elsevier Ltd. All rights reserved
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