【摘 要】
：
Missense mutations in RyR2 underlie the condition CPVT, which is associated with cardiac arrhythmias during exercise or stress.CPVT mutations occur in 3 clusters, corresponding to the N-terminal, cent
【机 构】
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Biological Sciences University of Leeds UK
【出 处】
：
BITs 1rd Annual World Cancer Congress of Cardiology-2009(200
论文部分内容阅读
Missense mutations in RyR2 underlie the condition CPVT, which is associated with cardiac arrhythmias during exercise or stress.CPVT mutations occur in 3 clusters, corresponding to the N-terminal, central and the pore-forming regions of RyR2 (or regions 1, 2 & 3 respectively).A similar clustering of RyR1 mutations occurs in the skeletal muscle disease MH.Recent evidence suggests that (ⅰ) mutations in regions 1 and 2 occur within interacting domains and (ⅱ) region 3 is actually another pair of interacting domains.If this hypothesis is correct, it should be possible to mimic the effects of specific mutations using RyR2 peptides, which act competitively to disrupt the interdomain interactions.Here we report the effects of a peptide (DPc10), which binds competitively to region 2 of RyR2, thereby disrupting interactions between regions 1 and 2 and mimicking the disease phenotype.Rats (Wistar, 200g) were humanely killed in accordance with UK legislation and ventricular myocytes isolated enzymatically.Cells were permeabilized with saponin (5μg/ml) and perfused with a mock intracellular solution containing (mM)ATP 5, phosphocreatine 10, HEPES 15 (free Ca2+ 200 nM, Mg2+ 1mM.pH 7.1, 21oC).Solutions also contained fluo-3 (10μM), allowing changes in cytosolic [Ca2+] to be detected using confocal microscopy.
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