How calcium channels in muscle cells open together
Every step we take begins with a burst of calcium inside our muscle cells, causing them to contract. To prepare for action, the cells keep calcium locked in an internal compartment, the sarcoplasmic reticulum. Studding its membrane are thousands of RyR1 channels—the largest known ion channels—that contain pores that release the calcium. For a muscle to contract properly, RyR1 channels must open…
Calcium channels in muscle cells open simultaneously, a process known as coupled gating. This mechanism allows muscle contraction to proceed smoothly. Scientists have recently captured the first high-resolution 3D images of these channels, RyR1, at various stages of opening within the sarcoplasmic reticulum membrane. The study, published in Nature Communications, was led by Dr. Vasilii Mikirtumov and conducted at the Max Delbrück Center.
Previously, studies on RyR1 were based on channels removed from the membrane, but this research focused on the structure of the channel in its natural environment using advanced imaging techniques like cryo-electron microscopy and tomography. The findings revealed that neighboring channels remain in contact with each other during the transition from closed to open states. This contact, or interface, is crucial for coupled gating, as it allows one channel to prime its neighbor for rotation and opening.
The researchers compared the structures of RyR1 at six stages of opening and observed that the bulky outer part of the channel rotates within the membrane plane, while the pore widens to approximately twice its original width. Additionally, imaging pairs of neighboring channels at five stages of opening showed that they were more likely to be synchronized and that two interacting closed channels were more stable than isolated closed channels.
These findings support the concept of coupled gating and suggest that channels hold each other shut.
Mutations in the RYR1 gene, which leads to conditions like malignant hyperthermia and congenital myopathies, often affect the interface where channels touch their neighbors. The researchers believe that disruptions at this interface may cause channels to leak calcium, leading to instability and potential disease. By understanding the normal organization of the interface, the team aims to design interventions that stabilize the closed state, potentially serving as therapeutic targets for these conditions.
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