Phosphorylation of RyR2 simultaneously expands the dyad and rearranges the tetramers

• DOI: 10.1085/jgp.202213108
• Publication Date: 2024-02-22T14:35:29Z
• Authors: Parisa Asghari; David R.L. Scriven; Saba Shahrasebi; Hector H. Valdivia; Katherina M. Alsina; Carmen R. Valdivia; J. Alberto Navarr...; Xander H.T. Wehrens; Edwin D.W. Moore
• Keywords: Tetramer

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 determine whether of RyR2 was an essential element the response. Here, we used β-agonist isoproterenol and mice homozygous for one following clinically relevant mutations: S2030A, S2808A, S2814A, or S2814D. measured length dyad using transmission electron microscopy (TEM) directly visualized distribution dual-tilt tomography. found S2814D mutation, by itself, significantly expanded reorganized tetramers, suggesting direct link between state tetramer its microarchitecture. S2808A S2814A mutant mice, as well wild types, had significant expansions their dyads isoproterenol, while S2030A mutants did not. In agreement with functional data from these mutants, S2030 S2808 were necessary complete β-adrenergic response, unlike S2814 mutants. Additionally, all unique effects on organization arrays. Lastly, correlation structural changes suggests tetramer–tetramer contacts play important role. thus conclude both size arrangement are linked channel dynamically altered receptor agonist.