The binding of the RyR2 calcium channel to its gating protein FKBP12.6 is oppositely affected by ARVD2 and VTSIP mutations

被引:41
作者
Tiso, N [1 ]
Salamon, M [1 ]
Bagattin, A [1 ]
Danieli, GA [1 ]
Argenton, F [1 ]
Bortolussi, M [1 ]
机构
[1] Univ Padua, Dept Biol, I-35131 Padua, Italy
关键词
ARVD2; VTSIP; cardiac; mutation; RyR2; channel; FKBP12.6; FK506; RyR1; yeast;
D O I
10.1016/S0006-291X(02)02689-X
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Arrhythmogenic right ventricular dysplasia/cardiomyopathy type 2 (ARVD2, OMIM 600996) and stress-induced polymorphic ventricular tachycardia (VTSIP, OMIM 604772) are two cardiac diseases causing juvenile sudden death, both associated with mutations in the RyR2 calcium channel. By using a quantitative yeast two-hybrid system, we show that VTSIP- and ARVD2-associated point mutations influence positively and negatively, respectively, the binding of RyR2 to its gating protein FKBP12.6. These findings suggest that ARVD2 mutations increase RyR2-mediated calcium release to cytoplasm, while VTSIP mutations do not affect significantly cytosolic calcium levels, thereby explaining the clinical differences between the two diseases. The present two-hybrid system appears to be an efficient molecular tool to assay the binding of FKBP12s proteins to both cardiac RyR2 and skeletal muscle RyR1 isoforms, circumventing the full-length expression of this class of giant channels. We also provide evidence of the suitability of this system to test new drugs that target RyRs-FKBP12s interactions and do not affect yeast growth. (C) 2002 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:594 / 598
页数:5
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