Ligand-induced activation of RyR1 in native membranes

Abstract Synchronized calcium release through arrays of the ryanodine receptor RyR1, fundamental to skeletal muscle excitation-contraction coupling, is achieved through the mechanical interaction of RyR1s and voltage-sensing receptors DHPR that activate RyR1s in response to action potentials. The calcium release is enhanced through “coupled gating”, when the activation of one channel promotes the opening of its neighbours. Here, we determine high-resolution structures of RyR1 in native sarcoplasmic reticulum membranes by cryo-EM/ET, capturing the conformations along the activation pathway and corner-to-corner interfaces between adjacent RyR1 receptors. Compared with purified RyR1s, receptors in native membranes follow an activation pathway with reduced cytosolic-shell tilt and greater consecutive in-plane rotation. Activation-induced rotation remodels the inter-receptor interface, lowering the energy barrier to the cooperative opening of the receptor cluster. Our analysis demonstrates how the native membrane receptor lattice influences ion channel cluster dynamics and provides a mechanistic framework for understanding calcium signaling in muscle.