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- Title
Molecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations.
- Authors
Kobayashi, Takuya; Tsutsumi, Akihisa; Kurebayashi, Nagomi; Saito, Kei; Kodama, Masami; Sakurai, Takashi; Kikkawa, Masahide; Murayama, Takashi; Ogawa, Haruo
- Abstract
Cardiac ryanodine receptor (RyR2) is a large Ca2+ release channel in the sarcoplasmic reticulum and indispensable for excitation-contraction coupling in the heart. RyR2 is activated by Ca2+ and RyR2 mutations are implicated in severe arrhythmogenic diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remains unknown. Here, we address the gating mechanism of RyR2 by combining high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated two fundamental mechanisms for channel gating: interactions close to the channel pore stabilize the channel to prevent hyperactivity and a series of interactions in the surrounding regions is necessary for channel opening upon Ca2+ binding. Mutations at the residues involved in the former and the latter mechanisms cause gain-of-function and loss-of-function, respectively. Our results reveal gating mechanisms of the RyR2 channel and alterations by pathogenic mutations at the atomic level. Ryanodine receptor 2 (RyR2) is a Ca2+ release channel essential for cardiac excitation-contraction coupling. Here, the authors use structural and functional analysis to reveal RyR2 gating mechanism and its alterations by pathogenic mutations.
- Subjects
RYANODINE receptors; CALCIUM channels; SARCOPLASMIC reticulum; STEREOLOGY; FUNCTIONAL analysis
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-022-30429-x