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The ryanodine receptor store-sensing gate controls Ca 2+ waves and Ca2+-triggered arrhythmias

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收录情况： ◇ 自然指数

作者：
Chen, W[a] * ; Wang, R[a] ; Chen, B[b] ; Zhong, X[a,g] ; Kong, H[a] ; Bai, Y[a,f] ; Zhou, Q[a,f] ; Xie, C[a,f,g] ; Zhang, J[c] ; Guo, A[b] ; Tian, X[a] ; Jones, P.P[a,f,h] ; O'Mara, M.L[d] ; Liu, Y[a] ; Mi, T[a,g] ; Zhang, L[a] ; Bolstad, J[a] ; Semeniuk, L[a] ; Cheng, H[e,f,i] ; Zhang, J[e,f] ; Chen, J[e] ; Tieleman, D.P[d] ; Gillis, A.M[a] ; Duff, H.J[a] ; Fill, M[c] ; Song, L.-S[b] ; Chen, S.R.W[a,c] ;
单位： [a]Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada [b]Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver, Iowa City, IA, United States [c]Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, United States [d]Department of Biological Sciences, Institute for Biocomplexity and Informatics, University of Calgary, Calgary, AB, Canada [e]Department of Medicine, University of California, San Diego, CA, United States [f]Department of Pharmacology, Ministry of Education, Harbin Medical University, Harbin, China [g]Department of Cardiology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China [h]Department of Physiology, University of Otago, Dunedin, New Zealand [i]Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University, Hangzhou, China
出处：
DOI： 10.1038/nm.3440
ISSN：

摘要：
Spontaneous Ca 2+ release from intracellular stores is important for various physiological and pathological processes. In cardiac muscle cells, spontaneous store overload-induced Ca 2+ release (SOICR) can result in Ca 2+ waves, a major cause of ventricular tachyarrhythmias (VTs) and sudden death. The molecular mechanism underlying SOICR has been a mystery for decades. Here we show that a point mutation, E4872A, in the helix bundle crossing region (the proposed gate) of the cardiac ryanodine receptor (RyR2) completely abolishes luminal, but not cytosolic, Ca 2+ activation of RyR2. The introduction of metal-binding histidines at this site converts RyR2 into a luminal Ni 2+-gated channel. Mouse hearts harboring a heterozygous RyR2 mutation at this site (E4872Q) are resistant to SOICR and are completely protected against Ca 2+-triggered VTs. These data show that the RyR2 gate directly senses luminal (store) Ca 2+, explaining the regulation of RyR2 by luminal Ca 2+, the initiation of Ca 2+ waves and Ca 2+-triggered arrhythmias. This newly identified store-sensing gate structure is conserved in all RyR and inositol 1,4,5-trisphosphate receptor isoforms. © 2014 Nature America, Inc.

基金：
This work was supported by research grants from the Canadian Institutes of Health Research (CIHR) to H.J.D., D.P.T. and S.R.W.C., the US National Institutes of Health to J.C., L.-S.S., M.F. and S.R.W.C., the Heart and Stroke Foundation of Alberta to A.M.G., H.J.D. and S.R.W.C. and the Canada Foundation for Innovation (S.R.W.C.) and by the Heart and Stroke Foundation/Libin Cardiovascular Institute Professorship in Cardiovascular Research (S.R.W.C.). We are grateful for generous donations from the King family, the Howarth family and the Libin Cardiovascular Institute of Alberta. We are also grateful to W.C. Claycomb from the Louisiana State University Health Sciences Center for kindly providing the HL-1 cardiac cell line and to J. Lytton from the University of Calgary for the gift of the β-actin–specific antibody. W.C., X.Z. and X.T. are recipients of the Alberta Innovates-Health Solutions (AIHS) Studentship Award; P.P.J. is a recipient of AIHS and Heart and Stroke Foundation Fellowship Awards; M.L.O. is the recipient of a CIHR Fellowship Award; and H.J.D., D.P.T. and S.R.W.C. are recipients of AIHS Scientist Awards.
语种：
外文
中科院(CAS)分区：
出版当年[2013]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学 1 区 医学：研究与实验
最新[2025]版：
大类 | 1 区 医学
小类 | 1 区 生化与分子生物学 1 区 细胞生物学 1 区 医学：研究与实验
第一作者：
第一作者单位： [a]Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
通讯作者：
通讯机构： [a]Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada [c]Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, IL, United States
推荐引用方式(GB/T 7714)：
Chen W,Wang R,Chen B,et al.The ryanodine receptor store-sensing gate controls Ca 2+ waves and Ca2+-triggered arrhythmias[J].Nature Medicine.2014,20(2):doi:10.1038/nm.3440.
APA：
Chen, W,Wang, R,Chen, B,Zhong, X,Kong, H...&Chen, S.R.W.(2014).The ryanodine receptor store-sensing gate controls Ca 2+ waves and Ca2+-triggered arrhythmias.Nature Medicine,20,(2)
MLA：
Chen, W,et al."The ryanodine receptor store-sensing gate controls Ca 2+ waves and Ca2+-triggered arrhythmias".Nature Medicine 20..2(2014)

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