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Identification of an amino-terminus determinant critical for ryanodine receptor/Ca2+ release channel function.
Seidel, Monika; de Meritens, Camille Rabesahala; Johnson, Louisa; Parthimos, Dimitris; Bannister, Mark; Thomas, Nia Lowri; Ozekhome-Mike, Esizaze; Lai, Francis Anthony; Zissimopoulos, Spyros.
Afiliação
  • Seidel M; Department of Cardiology, School of Medicine, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  • de Meritens CR; Swansea University Medical School, Institute of Life Science, Swansea SA2 8PP, UK.
  • Johnson L; Department of Cardiology, School of Medicine, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  • Parthimos D; Swansea University Medical School, Institute of Life Science, Swansea SA2 8PP, UK.
  • Bannister M; Department of Cardiology, School of Medicine, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  • Thomas NL; Swansea University Medical School, Institute of Life Science, Swansea SA2 8PP, UK.
  • Ozekhome-Mike E; Department of Cardiology, School of Medicine, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
  • Lai FA; Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
  • Zissimopoulos S; Department of Cardiology, School of Medicine, Wales Heart Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
Cardiovasc Res ; 117(3): 780-791, 2021 02 22.
Article em En | MEDLINE | ID: mdl-32077934
AIMS: The cardiac ryanodine receptor (RyR2), which mediates intracellular Ca2+ release to trigger cardiomyocyte contraction, participates in development of acquired and inherited arrhythmogenic cardiac disease. This study was undertaken to characterize the network of inter- and intra-subunit interactions regulating the activity of the RyR2 homotetramer. METHODS AND RESULTS: We use mutational investigations combined with biochemical assays to identify the peptide sequence bridging the ß8 with ß9 strand as the primary determinant mediating RyR2 N-terminus self-association. The negatively charged side chains of two aspartate residues (D179 and D180) within the ß8-ß9 loop are crucial for the N-terminal inter-subunit interaction. We also show that the RyR2 N-terminus domain interacts with the C-terminal channel pore region in a Ca2+-independent manner. The ß8-ß9 loop is required for efficient RyR2 subunit oligomerization but it is dispensable for N-terminus interaction with C-terminus. Deletion of the ß8-ß9 sequence produces unstable tetrameric channels with subdued intracellular Ca2+ mobilization implicating a role for this domain in channel opening. The arrhythmia-linked R176Q mutation within the ß8-ß9 loop decreases N-terminus tetramerization but does not affect RyR2 subunit tetramerization or the N-terminus interaction with C-terminus. RyR2R176Q is a characteristic hypersensitive channel displaying enhanced intracellular Ca2+ mobilization suggesting an additional role for the ß8-ß9 domain in channel closing. CONCLUSION: These results suggest that efficient N-terminus inter-subunit communication mediated by the ß8-ß9 loop may constitute a primary regulatory mechanism for both RyR2 channel activation and suppression.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article