The ryanodine receptor store-sensing gate controls Ca2+ waves and Ca2+-triggered arrhythmias.
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.
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Wenqian
W
Chen
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Ruiwu
R
Wang
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Biyi
B
Chen
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Xiaowei
X
Zhong
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Huihui
H
Kong
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2].
Yunlong
Y
Bai
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2].
Qiang
Q
Zhou
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2].
Cuihong
C
Xie
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA.
Jingqun
J
Zhang
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Ang
A
Guo
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Xixi
X
Tian
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2].
Peter P
PP
Jones
Department of Biological Sciences and Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Alberta, Canada.
Megan L
ML
O'Mara
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Yingjie
Y
Liu
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2].
Tao
T
Mi
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Lin
L
Zhang
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Jeff
J
Bolstad
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Lisa
L
Semeniuk
1] Department of Medicine, University of California at San Diego, La Jolla, California, USA. [2].
Hongqiang
H
Cheng
Department of Medicine, University of California at San Diego, La Jolla, California, USA.
Jianlin
J
Zhang
Department of Medicine, University of California at San Diego, La Jolla, California, USA.
Ju
J
Chen
Department of Biological Sciences and Institute for Biocomplexity and Informatics, University of Calgary, Calgary, Alberta, Canada.
D Peter
DP
Tieleman
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Anne M
AM
Gillis
The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada.
Henry J
HJ
Duff
Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA.
Michael
M
Fill
Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA.
Long-Sheng
LS
Song
1] The Libin Cardiovascular Institute of Alberta, Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada. [2] Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, USA.
S R Wayne
SR
Chen
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism*; D002110:Caffeine; D002118:Calcium / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D004452:Echocardiography; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008051:Lipid Bilayers / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D016297:Mutagenesis, Site-Directed; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D017354:Point Mutation / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D008051:Lipid Bilayers; D019837:Ryanodine Receptor Calcium Release Channel; D002110:Caffeine; D002118:Calcium