Phosphorylation of RyR2 simultaneously expands the dyad and rearranges the tetramers.

Autor:	Asghari P; Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada., Scriven DRL; Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada., Shahrasebi S; Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada., Valdivia HH; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA., Alsina KM; Castle Biosciences Inc. , Friendswood, TX, USA., Valdivia CR; Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA., Navarro-Garcia JA; Department of Integrative Physiology, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA., Wehrens XHT; Department of Integrative Physiology, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA., Moore EDW; Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
Jazyk:	angličtina
Zdroj:	The Journal of general physiology [J Gen Physiol] 2024 Apr 01; Vol. 156 (4). Date of Electronic Publication: 2024 Feb 22.
DOI:	10.1085/jgp.202213108
Abstrakt:	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. (© 2024 Asghari et al.)
Databáze:	MEDLINE
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