Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation

Autor: Yuriana Aguilar-Sanchez, Olivier Villejoubert, Feliciano Protasi, Liheng Yin, Camille Rabesahala de Meritens, Julio L. Álvarez, Pascale Gerbaud, Ernst Niggli, Romain Perrier, Pierre Joanne, Héctor H. Valdivia, F. Anthony Lai, Spyros Zissimopoulos, Riccardo Rizzetto, Esther Zorio, Elena Marques-Sule, Linwei Li, Yue Yi Wang, Yadan Zhang, Alexandra Zahradnikova Jr, Carmen R. Valdivia, Simona Boncompagni, Jean-Pierre Benitah, Valérie Nicolas, Ana Maria Gomez, Josefina Ramos-Franco, Philippe Mateo, Miguel Fernandez-Tenorio
Přispěvatelé: Signalisation et physiopathologie cardiovasculaire (CARPAT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Università degli studi 'G. d'Annunzio' Chieti-Pescara [Chieti-Pescara] (Ud'A), Institute of Life Science [Swansea], Swansea University, Rush University Medical Center [Chicago], University of Bern, Ingénierie et Plateformes au Service de l'Innovation Thérapeutique (IPSIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Qatar University, University of Wisconsin-Madison, Hospital Universitari i Politècnic La Fe, Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV)
Rok vydání: 2021
Předmět:
Zdroj: CIRCULATION RESEARCH
r-IIS La Fe. Repositorio Institucional de Producción Científica del Instituto de Investigación Sanitaria La Fe
instname
Circulation Research
Circulation Research, American Heart Association, 2021, 129 (3), pp.e35-e52. ⟨10.1161/CIRCRESAHA.121.319094⟩
Circ Res
ISSN: 0009-7330
1524-4571
DOI: 10.1161/CIRCRESAHA.121.319094⟩
Popis: Rationale: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare disease, manifested by syncope or sudden death in children or young adults under stress conditions. Mutations in the Ca 2+ release channel/RyR2 (type 2 ryanodine receptor) gene account for about 60% of the identified mutations. Recently, we found and described a mutation in RyR2 N-terminal domain, RyR2 R420Q . Objective: To determine the arrhythmogenic mechanisms of this mutation. Methods and Results: Ventricular tachycardias under stress conditions were observed in both patients with catecholaminergic polymorphic ventricular tachycardia and knock-in mice. During action potential recording (by patch-clamp in knock-in mouse cardiomyocytes and by microelectrodes in mutant human induced pluripotent stem cell-derived cardiomyocytes), we observed an increased occurrence of delayed afterdepolarizations under isoproterenol stimulation, associated with increased Ca 2+ waves during confocal Ca 2+ recording in both mouse and human RyR2 R420Q cardiomyocytes. In addition, Ca 2+ -induced Ca 2+ -release, as well as a rough indicator of fractional Ca 2+ release, were higher and Ca 2+ sparks longer in the RyR2 R420Q -expressing cells. At the ultrastructural nanodomain level, we observed smaller RyR2 clusters and widened junctional sarcoplasmic reticulum measured by gated stimulated emission depletion super-resolution and electron microscopy, respectively. The increase in junctional sarcoplasmic reticulum width might be due to the impairment of RyR2 R420Q binding to JPH2 (junctophilin-2), as there were less junctophilin-2 coimmunoprecipitated with RyR2 R420Q . At the single current level, the RyR2 R420Q channel dwells longer in the open state at low intracellular Ca 2+ ([Ca 2+ ] i ), but there is predominance of a subconductance state. The latter might be correlated with an enhanced interaction between the N terminus and the core solenoid, a RyR2 interdomain association that has not been previously implicated in the pathogenesis of arrhythmias and sudden cardiac death. Conclusions: The RyR2 R420Q catecholaminergic polymorphic ventricular tachycardia mutation modifies the interdomain interaction of the channel and weakens its association with JPH2. These defects may underlie both nanoscale disarrangement of the dyad and channel dysfunction.
Databáze: OpenAIRE
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