Cardiac ryanodine receptor distribution is dynamic and changed by auxiliary proteins and post-translational modification

Author:

Asghari Parisa1ORCID,Scriven David RL1ORCID,Ng Myles1,Panwar Pankaj2,Chou Keng C3,van Petegem Filip2ORCID,Moore Edwin DW1ORCID

Affiliation:

1. Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada

2. Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, Canada

3. Department of Chemistry, University of British Columbia, Vancouver, Canada

Abstract

The effects of the immunophilins, FKBP12 and FKBP12.6, and phosphorylation on type II ryanodine receptor (RyR2) arrangement and function were examined using correlation microscopy (line scan confocal imaging of Ca2+ sparks and dual-tilt electron tomography) and dSTORM imaging of permeabilized Wistar rat ventricular myocytes. Saturating concentrations (10 µmol/L) of either FKBP12 or 12.6 significantly reduced the frequency, spread, amplitude and Ca2+ spark mass relative to control, while the tomograms revealed both proteins shifted the tetramers into a largely side-by-side configuration. Phosphorylation of immunophilin-saturated RyR2 resulted in structural and functional changes largely comparable to phosphorylation alone. dSTORM images of myocyte surfaces demonstrated that both FKBP12 and 12.6 significantly reduced RyR2 cluster sizes, while phosphorylation, even of immunophilin-saturated RyR2, increased them. We conclude that both RyR2 cluster size and the arrangement of tetramers within clusters is dynamic and respond to changes in the cellular environment. Further, these changes affect Ca2+ spark formation.

Funder

Canadian Institutes of Health Research

Natural Sciences and Engineering Research Council of Canada

Canada Foundation for Innovation

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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