High-Resolution Structures Show How Muscle Calcium Channels Open Together

Overview

• A Nature Communications paper published Thursday presents the first high-resolution 3D reconstructions of type-1 ryanodine receptor (RyR1) channels inside intact sarcoplasmic reticulum membranes, captured at six stages of opening.
• The structures show corner-to-corner contacts between adjacent RyR1 channels that transmit mechanical strain when one channel rotates open, which primes neighbors to open synchronously in a process called coupled gating.
• Researchers used cryo-electron microscopy and cryo-electron tomography on rabbit muscle sarcoplasmic reticulum and averaged thousands of images to resolve the channel rotation and the pore widening to roughly twice its closed diameter.
• Mapping known RYR1 disease variants onto the inter-channel interface links many malignant hyperthermia and congenital myopathy mutations to disrupted cooperation between channels rather than to single-channel pore defects.
• The team is now testing ways to stabilize the closed state and design biologics or small molecules that target the inter-channel interface, but therapeutic efforts are at an early, experimental stage.