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AuthorYin, Liheng
AuthorJr, Alexandra Zahradnikova
AuthorRizzetto, Riccardo
AuthorBoncompagni, Simona
AuthorMeritens, Camille Rabesahala de
AuthorZhang, Yadan
AuthorJoanne, Pierre
AuthorMarqués-Sulé, Elena
AuthorAguilar-Sánchez, Yuriana
AuthorFernández-Tenorio, Miguel
AuthorVillejoubert, Olivier
AuthorLi, Linwei
AuthorWang, Yue Yi
AuthorMateo, Philippe
AuthorNicolas, Valérie
AuthorGerbaud, Pascale
AuthorLai, F. Anthony
AuthorPerrier, Romain
AuthorÁlvarez, Julio L.
AuthorNiggli, Ernst
AuthorValdivia, Héctor H.
AuthorValdivia, Carmen R.
AuthorRamos-Franco, Josefina
AuthorZorio, Esther
AuthorZissimopoulos, Spyros
AuthorProtasi, Feliciano
AuthorBenitah, Jean-Pierre
AuthorGómez, Ana M.
Available date2021-08-08T10:12:04Z
Publication Date2021-07-23
Publication NameCirculation Research
AbstractRATIONALE: Catecholaminergic polymorphic ventricular tachycardia is a rare disease, manifested by syncope or sudden death in children or young adults under stress conditions. Mutations in the Ca2+ release channel/type 2 ryanodine receptor (RyR2) gene account for about 60% of the identified mutations. Recently, we found and described a mutation in RyR2 N-terminal domain, RyR2R420Q. 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 Ca2+ waves during confocal Ca2+ recording in both mouse and human RyR2R420Q cardiomyocytes. In addition, Ca2+-induced Ca2+-release, as well as a rough indicator of fractional Ca2+ release, were higher and Ca2+ sparks longer in the RyR2R420Q-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 electronic microscopy, respectively. The increase in junctional sarcoplasmic reticulum width might be due to the impairment of RyR2R420Q binding to junctophilin-2, as there were less junctophilin-2 coimmunoprecipitated with RyR2R420Q. At the single current level, the RyR2R420Q channel dwells longer in the open state at low intracellular Ca2+ ([Ca2+]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 RyR2R420Q catecholaminergic polymorphic ventricular tachycardia mutation modifies the interdomain interaction of the channel and weakens its association with junctophillin-2. These defects may underlie both nanoscale disarrangement of the dyad and channel dysfunction. GRAPHIC ABSTRACT: An online graphic abstract is available for this article.
SponsorThis work was funded by Inserm and University Paris-Sud, and grants from ANR (ANR-19-CE14-0031-01 to A.M. Gómez), LabEx LERMIT (ANR-10-LABX-33), “Instituto de Salud Carlos III”; FEDER “Union Europea, Una forma de hacer Europa” (PI18/01582), La Fe Biobank (PT17/0015/0043) and Memorial Nacho Barberá to E. Zorio; Swiss National Science Foundation (SNSF grants no. 31003A 179325 and 310030 156375 to E. Niggli), British Heart Foundation (FS/15/30/31494) to S. Zissimopoulos; Italian Telethon ONLUS Foundation (GGP19231) and Italian MIUR (PRIN no. 2015ZZR4W3) to F. Protasi; National Institutes of Health (NIH) grants to J. Ramos-Franco (R01GM111397) and H.H. Valdivia–A.M. Gómez (2R01HL055438-22); and European Union H2020 (MSCA-RISE AMD-734931- 6) to A.M. Gómez. H.H. Valdivia was recipient of a Fullbright-Tockeville chair to work on A.M. Gómez laboratory. J.L. Álvarez and C.R. Valdivia were recipient of a visiting program Alambert from University Paris-Sud to work in A.M. Gómez laboratory. A. Zahradnikova was recipient of a postdoctoral position from University Paris-Sud. R. Rizzetto was recipient of a postdoctoral fellowship from CORDDIM (Région Ile de France). L. Yin was recipient of the CSC (Chinese Scholarship council).
PublisherAmerican Heart Association
Subjectryanodine receptor
ventricular tachycardia
action potential
TitleImpaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation
Issue Number3
Volume Number129

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