Molecular basis for gating of cardiac ryanodine receptor: underlying mechanisms for gain- and loss-of function mutations

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 have been implicated in severe arrhythmogenic heart diseases. Yet, the structural basis underlying channel opening and how mutations affect the channel remain unknown. Here, we combined high-resolution structures determined by cryo-electron microscopy with quantitative functional analysis of channels carrying various mutations in specific residues. We demonstrated that interactions close to the channel pore are important for stabilizing the channel in the closed state and those in the surrounding regions are essential for channel opening. Our results reveal mechanisms underlying channel opening upon Ca2+ binding and alterations by pathogenic mutations of RyR2 at the atomic level.One Sentence SummaryKey movements and interactions in RyR2 during cardiac Ca2+ channel opening are clarified at the atomic level.