Muscle Cell Calcium Channel Structure, Synchronicity Could Advance Muscle Disease Therapeutics

Muscle contraction begins with a surge of calcium inside muscle cells, prompting them to contract. Researchers at the Max Delbrück Center have used cryo-electron microscopy (cryo-EM) to reveal how calcium channels called type-1 ryanodine receptors (RyR1) open in synchrony within these cells. These findings, published in Nature Communications, could shed light on the mechanisms behind severe muscle diseases and potentially lead to new therapeutic strategies.

RyR1 channels, the largest known ion channels, are responsible for releasing calcium from internal stores into the cell when a muscle contracts. However, the precise mechanism by which RyR1 channels open simultaneously—known as "coupled gating"—has remained a mystery since it was first described nearly three decades ago. Using advanced imaging techniques, the Max Delbrück Center team, led by Dr. Vasilii Mikirtumov, has captured the highest-resolution 3D images of RyR1 at six stages of opening within the natural sarcoplasmic reticulum membrane.

The sarcoplasmic reticulum is the internal compartment where calcium is typically stored. The researchers isolated the sarcoplasmic reticulum from rabbit muscle and imaged it using cryo-EM and tomography techniques. By comparing the structures of RyR1 at different stages of opening, the team discovered that the bulk of the receptor rotates within the plane of the membrane like turning the ring of a camera lens, while the pore widens to roughly twice its original size.

This coordinated motion, called "coupled gating," allows neighboring RyR1 channels to remain in contact with each other when transitioning from a closed to an open state. This interface, or the "interface" where the channels touch, mediates the coordination of their opening. The researchers compared the structures of RyR1 at four distinct and two intermediate functional states, discovering that the activation of RyR1 involves a significant rotation component in the membrane plane.

Additionally, imaging pairs of neighboring channels revealed that they are more likely to open synchronously when they are in contact with each other. Mutations in the RYR1 gene, responsible for many muscle diseases, often occur precisely where the channels touch their neighbors. The researchers propose that disruptions at this interface can cause channels to become leaky, releasing calcium prematurely.

Consequently, they suggest that targeting this interface could be a promising therapeutic approach for treating RyR1-associated skeletal muscle diseases.