Clustering properties of the cardiac ryanodine receptor in health and heart failure

Waddell, Helen M.M.; Mereacre, Valeria; Alvarado, Francisco J.; Munro, Michelle L.

doi:10.1016/j.yjmcc.2023.10.012

Cited by 5 publications

(1 citation statement)

References 117 publications

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“…Although this is technically challenging there have been recent advances in the field. For example, a transgeneic mouse with a photactivated label on RyR2 has been recently generated ( 37 ). To understand the functional differences in basal phenotype and pharmacological response in RYR2 Het KO vs. WT cardiomyocytes, an unbiased proteomics approach was taken.…”

Section: Discussionmentioning

confidence: 99%

RYR2 deficient human model identifies calcium handling and metabolic dysfunction impacting pharmacological responses

Starnes,

Hall,

Etal

et al. 2024

Front. Cardiovasc. Med.

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Creation of disease models utilizing hiPSCs in combination with CRISPR/Cas9 gene editing enable mechanistic insights into differential pharmacological responses. This allows translation of efficacy and safety findings from a healthy to a diseased state and provides a means to predict clinical outcome sooner during drug discovery. Calcium handling disturbances including reduced expression levels of the type 2 ryanodine receptor (RYR2) are linked to cardiac dysfunction; here we have created a RYR2 deficient human cardiomyocyte model that mimics some aspects of heart failure. RYR2 deficient cardiomyocytes show differential pharmacological responses to L-type channel calcium inhibitors. Phenotypic and proteomic characterization reveal novel molecular insights with altered expression of structural proteins including CSRP3, SLMAP, and metabolic changes including upregulation of the pentose phosphate pathway and increased sensitivity to redox alterations. This genetically engineered in vitro cardiovascular model of RYR2 deficiency supports the study of pharmacological responses in the context of calcium handling and metabolic dysfunction enabling translation of drug responses from healthy to perturbed cellular states.

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Section: Discussionmentioning

confidence: 99%

RYR2 deficient human model identifies calcium handling and metabolic dysfunction impacting pharmacological responses

Starnes,

Hall,

Etal

et al. 2024

Front. Cardiovasc. Med.

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Quantitative Single-Molecule Analysis of Ryanodine Receptor 2 Subunit Assembly in Cardiac and Neuronal Tissues

Yin,

Aryal,

Song

et al. 2024

Anal. Chem.

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We developed a method for ex vivo receptor encapsulation and single-molecule imaging techniques from neuronal and cardiac tissues, illustrating the method’s broad applicability for measuring membrane receptor assembly. Ryanodine receptor 2 (RyR2) is a tetrameric Ca2+ channel governing intracellular Ca2+ dynamics, which is critical for muscle contraction. Employing GFP-RyR2 knock-in mice, we isolated individual receptor proteins in tissue-specific nanovesicles and performed subunit counting analyses to yield quantitative assessment of stoichiometric distributions across different organs. With this method, we explored the potential heterogeneity of brain-derived RyR2, which has been reported to form heteromeric assemblies with other ryanodine receptor isoforms.

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Time-dependent effect of FKBP12 loss in the development of dilated cardiomyopathy

Chan,

Munro

2024

Journal of General Physiology

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Clustering properties of the cardiac ryanodine receptor in health and heart failure

Cited by 5 publications

References 117 publications

RYR2 deficient human model identifies calcium handling and metabolic dysfunction impacting pharmacological responses

RYR2 deficient human model identifies calcium handling and metabolic dysfunction impacting pharmacological responses

Quantitative Single-Molecule Analysis of Ryanodine Receptor 2 Subunit Assembly in Cardiac and Neuronal Tissues

Time-dependent effect of FKBP12 loss in the development of dilated cardiomyopathy

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