Language
English
Publication Date
4-1-2024
Journal
The Journal of General Physiology
DOI
10.1085/jgp.202213108
PMID
38385988
PMCID
PMC10883851
PubMedCentral® Posted Date
2-22-2024
PubMedCentral® Full Text Version
Post-print
Abstract
We have previously demonstrated that type II ryanodine receptors (RyR2) tetramers can be rapidly rearranged in response to a phosphorylation cocktail. The cocktail modified downstream targets indiscriminately, making it impossible to determine whether phosphorylation of RyR2 was an essential element of the response. Here, we used the β-agonist isoproterenol and mice homozygous for one of the following clinically relevant mutations: S2030A, S2808A, S2814A, or S2814D. We measured the length of the dyad using transmission electron microscopy (TEM) and directly visualized RyR2 distribution using dual-tilt electron tomography. We found that the S2814D mutation, by itself, significantly expanded the dyad and reorganized the tetramers, suggesting a direct link between the phosphorylation state of the tetramer and its microarchitecture. S2808A and S2814A mutant mice, as well as wild types, had significant expansions of their dyads in response to isoproterenol, while S2030A mutants did not. In agreement with functional data from these mutants, S2030 and S2808 were necessary for a complete β-adrenergic response, unlike S2814 mutants. Additionally, all mutants had unique effects on the organization of their tetramer arrays. Lastly, the correlation of structural with functional changes suggests that tetramer–tetramer contacts play an important functional role. We thus conclude that both the size of the dyad and the arrangement of the tetramers are linked to the state of the channel tetramer and can be dynamically altered by a β-adrenergic receptor agonist.
Keywords
Animals, Mice, Isoproterenol, Mutation, Phosphorylation, Ryanodine Receptor Calcium Release Channel
Published Open-Access
yes
Recommended Citation
Asghari, Parisa; Scriven, David R L; Shahrasebi, Saba; et al., "Phosphorylation of RyR2 Simultaneously Expands the Dyad and Rearranges the Tetramers" (2024). Faculty and Staff Publications. 4012.
https://digitalcommons.library.tmc.edu/baylor_docs/4012