Preventing the phosphorylation of RyR2 at canonical sites reduces Ca2+ leak and promotes arrhythmia by reactivating the INa current

Jingjing Zheng; Daniela Ponce-Balbuena; Erick B. Rios Perez; Li Xiao; Holly C. Dooge; Hector H. Valdivia; Francisco J. Alvarado

doi:10.1038/s44161-025-00693-3

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Preventing the phosphorylation of RyR2 at canonical sites reduces Ca2+ leak and promotes arrhythmia by reactivating the INa current

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Preventing the phosphorylation of RyR2 at canonical sites reduces Ca2+ leak and promotes arrhythmia by reactivating the INa current

Jingjing Zheng, Daniela Ponce-Balbuena, Erick B. Rios Perez, Li Xiao, Holly C. Dooge, Hector H. Valdivia and Francisco J. Alvarado

NATURE CARDIOVASCULAR RESEARCH, Vol.4(8), pp.976-990

08/01/2025

DOI: 10.1038/s44161-025-00693-3

PMID: 40797044

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Abstract

Phosphorylation of specific sites in ryanodine receptor 2 (RyR2), a major cardiac Ca2+ channel, increases channel activity and promotes pathological sarcoplasmic reticulum Ca2+ leak and arrhythmia. RyR2 is phosphorylated during adrenergic stimulation, but the role of this phosphorylation remains debated. In this study, we generated a mouse model with phospho-ablation of the three canonical phosphorylation sites in RyR2 (S2031A/S2808A/S2814A, triple phospho-mutant (TPM)) to determine their role in the adrenergic response. TPM mice have normal basal cardiac structure and function. Isoproterenol stimulation produced normal chronotropic and inotropic responses in TPM mice and cardiomyocytes, which also showed reduced RyR2-mediated Ca2+ leak. However, TPM mice were susceptible to cardiac arrhythmias. These arrhythmias required systolic Ca2+ release and were induced by the reactivation of INa and early afterdepolarizations. We propose that phosphorylation of these residues in RyR2 is dispensable for chronotropy and inotropy; however, they maintain electrical stability during adrenergic stimulation by modulating a physiological RyR2-mediated Ca2+ leak.

Cardiac & Cardiovascular Systems

Cardiovascular System & Cardiology

Life Sciences & Biomedicine

Science & Technology

Details

Title: Subtitle: Preventing the phosphorylation of RyR2 at canonical sites reduces Ca2+ leak and promotes arrhythmia by reactivating the INa current
Creators: Jingjing Zheng - University of Wisconsin–Madison
Daniela Ponce-Balbuena - University of Wisconsin–Madison
Erick B. Rios Perez - University of Wisconsin–Madison
Li Xiao - University of Wisconsin–Madison
Holly C. Dooge - University of Wisconsin–Madison
Hector H. Valdivia - University of Wisconsin–Madison
Francisco J. Alvarado - University of Wisconsin–Madison
Resource Type: Journal article
Publication Details: NATURE CARDIOVASCULAR RESEARCH, Vol.4(8), pp.976-990
DOI: 10.1038/s44161-025-00693-3
PMID: 40797044
NLM abbreviation: Nat Cardiovasc Res
ISSN: 2731-0590
eISSN: 2731-0590
Publisher: Springer Nature
Number of pages: 29
Grant note: University of Wisconsin Department of Pathology and Laboratory Medicine; University of Wisconsin Madison S10 OD023526 / Office of the Director, National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) P30 CA014520 / University of Wisconsin Translational Research Initiatives in Pathology Laboratory; University of Wisconsin Madison RRID: SCR_024797; RRID: SCR_021070 / U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
Language: English
Date published: 08/01/2025
Academic Unit: Internal Medicine
Record Identifier: 9985178669902771

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