Journal article
Preserved cardiac performance and adrenergic response in a rabbit model with decreased ryanodine receptor 2 expression
Journal of molecular and cellular cardiology, Vol.167, pp.118-128
06/01/2022
DOI: 10.1016/j.yjmcc.2022.04.004
PMID: 35413295
Abstract
Ryanodine receptor 2 (RyR2) is an ion channel in the heart responsible for releasing into the cytosol most of the Ca2+ required for contraction. Proper regulation of RyR2 is critical, as highlighted by the association between channel dysfunction and cardiac arrhythmia. Lower RyR2 expression is also observed in some forms of heart disease; however, there is limited information on the impact of this change on excitation-contraction (e-c) coupling, Ca2+-dependent arrhythmias, and cardiac performance. We used a constitutive knock-out of RyR2 in rabbits (RyR2-KO) to assess the extent to which a stable decrease in RyR2 expression modulates Ca2+ handling in the heart. We found that homozygous knock-out of RyR2 in rabbits is embryonic lethal. Remarkably, heterozygotes (KO+/-) show ~50% loss of RyR2 protein without developing an overt phenotype at the intact animal and whole heart levels. Instead, we found that KO+/- myocytes show (1) remodeling of RyR2 clusters, favoring smaller groups in which channels are more densely arranged; (2) lower Ca2+ spark frequency and amplitude; (3) slower rate of Ca2+ release and mild but significant desynchronization of the Ca2+ transient; and (4) a significant decrease in the basal phosphorylation of S2031, likely due to increased association between RyR2 and PP2A. Our data show that RyR2 deficiency, although remarkable at the molecular and subcellular level, has only a modest impact on global Ca2+ release and is fully compensated at the whole-heart level. This highlights the redundancy of RyR2 protein expression and the plasticity of the e-c coupling apparatus.
Details
- Title: Subtitle
- Preserved cardiac performance and adrenergic response in a rabbit model with decreased ryanodine receptor 2 expression
- Creators
- Jingjing Zheng - University of Wisconsin–MadisonHolly C. Dooge - University of Wisconsin–MadisonMarta Perez-Hernandez - New York UniversityYan-Ting Zhao - University of MichiganXi Chen - University of MichiganJonathan J. Hernandez - University of Wisconsin–MadisonCarmen R. Valdivia - University of Wisconsin–MadisonJulieta Palomeque - Centro de Investigaciones CardiovascularesEli Rothenberg - New York UniversityMario Delmar - New York UniversityHector H. Valdivia - University of Wisconsin–MadisonFrancisco J. Alvarado - University of Wisconsin–Madison
- Resource Type
- Journal article
- Publication Details
- Journal of molecular and cellular cardiology, Vol.167, pp.118-128
- DOI
- 10.1016/j.yjmcc.2022.04.004
- PMID
- 35413295
- NLM abbreviation
- J Mol Cell Cardiol
- ISSN
- 0022-2828
- eISSN
- 1095-8584
- Publisher
- Elsevier
- Number of pages
- 11
- Grant note
- HL161070; HL055438; HL134344; HL134328; HL136179 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HL055438 / National Heart Lung and Blood Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) Heart Rhythm Society 19CDA34660208 / American Heart Association (AHA); American Heart Association University of Michigan Animal Phe-notyping Core 19CDA34660208 / Heart Rhythm Society HL161070; HL055438; HL134344; HL134328; HL136179 / Na-tional Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 19CDA34660208 / American Heart Association
- Language
- English
- Date published
- 06/01/2022
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985177946202771
Metrics
2 Record Views