Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes

Kolstad, T. R. et al. (2018) Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes. eLife, 7, pp. 1-24. e39427. (doi: 10.7554/eLife.39427) (PMID:30375974) (PMCID:PMC6245731)

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Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented ‘silent’ Ca2+ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca2+ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca2+ transient. Thus, nanoscale RyR reorganization during HF augments Ca2+ leak and slows Ca2+ release kinetics, leading to weakened contraction in this disease.

Item Type:Articles
Additional Information:Funding: Horizon 2020 Framework Programme (Consolidator grant for WEL 647714), Helse Sør-Øst RHF (2012072), Helse Sør-Øst RHF (2013014), Oslo University Hospital Ullevål, University of Oslo.
Keywords:Cell biology, rat, cardiomyocyte, medicine, ryanodine receptor, heart failure, Ca2+ spark, dSTORM, human biology.
Glasgow Author(s) Enlighten ID:MacQuaide, Dr Niall
Creator Roles:
MacQuaide, N.Conceptualization, Formal analysis, Investigation, Software, Visualization, Writing – original draft, Writing – review and editing
Authors: Kolstad, T. R., van den Brink, J., MacQuaide, N., Lunde, P. K., Frisk, M., Aronsen, J. M., Norden, E. S., Cataliotti, A., Sjaastad, I., Sejersted, O. M., Edwards, A. G., Lines, G. T., and Louch, W. E.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:eLife
Publisher:eLife Sciences Publications
ISSN (Online):2050-084X
Copyright Holders:Copyright © 2018 Kolstad et al.
First Published:First published in eLife 7:e39427
Publisher Policy:Reproduced under a Creative Commons License

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