Researchers from Juntendo University, Japan, studied the fifth segment (S5) of the type 1 ryanodine receptor (RyR1) channel, which is essential for muscle function. They discovered that changes in S5 can affect the channel’s work, leading to different muscle diseases, like malignant hyperthermia (MH) and central core disease (CCD).
This new information could help create better drugs and diagnostics for these severe muscle disorders.
The type 1 ryanodine receptor (RyR1) is crucial for muscle contraction by releasing calcium in muscle cells. Mutations in the RyR1 gene can cause severe muscle diseases: malignant hyperthermia (MH) from gain-of-function mutations and central core disease (CCD) from loss-of-function mutations.
Recent research led by Japanese researchers investigated the role of the fifth segment (S5) of RyR1, which needed to be better understood. They found that mutations in S5 affect how the RyR1 channel functions, contributing to these muscle disorders.
Researchers used HEK293 cells with RyR1 mutations to study calcium release. They tested how these mutations affected calcium dynamics using caffeine, fluorescent indicators, and ryanodine binding assays. They found three mutations linked to malignant hyperthermia (MH) and eight to central core disease (CCD).
MH mutations led to higher caffeine sensitivity and increased calcium release. In contrast, CCD mutations caused reduced calcium release and impaired channel function. Some CCD mutations even showed no detectable channel activity.
The researchers studied how mutations in the S5 segment of the RyR1 channel affect its function by analyzing its structure and interactions with other parts of the channel. They found that S5 plays a crucial role in regulating the channel.
This research improves our understanding of calcium signaling in muscles. It could lead to new drugs for treating muscle diseases caused by RyR1 mutations.
Journal reference :
- Takashi Murayama, Yuya Otori, et al., Dual role of the S5 segment in type 1 ryanodine receptor channel gating. Communications Biology. DOI: 10.1038/s42003-024-06787-1.
