کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10954017 | 1097830 | 2010 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The human CASQ2 mutation K206N is associated with hyperglycosylation and altered cellular calcium handling
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
بیولوژی سلول
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چکیده انگلیسی
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 CSQK206N were investigated in comparison to the wild-type form of CASQ2 (CSQWT) 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, CSQK206N-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 [3H]ryanodine binding was increased in CSQK206N-expressing myocytes, suggesting a higher opening state of the SR Ca2+ release channel. Myocytes with expression of CSQK206N showed a higher rate of spontaneous SR Ca2+ releases under basal conditions and after β-adrenergic stimulation. We conclude that CSQK206N 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 CSQK206N-expressing myocytes.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Molecular and Cellular Cardiology - Volume 49, Issue 1, July 2010, Pages 95-105
Journal: Journal of Molecular and Cellular Cardiology - Volume 49, Issue 1, July 2010, Pages 95-105
نویسندگان
Uwe Kirchhefer, Diana Wehrmeister, Alex V. Postma, Gottfried Pohlentz, Michael Mormann, Dana Kucerova, Frank U. Müller, Wilhelm Schmitz, Eric Schulze-Bahr, Arthur A. Wilde, Joachim Neumann,