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Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor
In cardiac muscle, the release of calcium ions from the sarcoplasmic reticulum through ryanodine receptor ion channels (RyR2s) leads to muscle contraction. RyR2 is negatively regulated by calmodulin (CaM) and by phosphorylation of Ca(2+)/CaM-dependent protein kinase II (CaMKII). Substitution of thre...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122402/ https://www.ncbi.nlm.nih.gov/pubmed/25093823 http://dx.doi.org/10.1371/journal.pone.0104338 |
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author | Chakraborty, Asima Pasek, Daniel A. Huang, Tai-Qin Gomez, Angela C. Yamaguchi, Naohiro Anderson, Mark E. Meissner, Gerhard |
author_facet | Chakraborty, Asima Pasek, Daniel A. Huang, Tai-Qin Gomez, Angela C. Yamaguchi, Naohiro Anderson, Mark E. Meissner, Gerhard |
author_sort | Chakraborty, Asima |
collection | PubMed |
description | In cardiac muscle, the release of calcium ions from the sarcoplasmic reticulum through ryanodine receptor ion channels (RyR2s) leads to muscle contraction. RyR2 is negatively regulated by calmodulin (CaM) and by phosphorylation of Ca(2+)/CaM-dependent protein kinase II (CaMKII). Substitution of three amino acid residues in the CaM binding domain of RyR2 (RyR2-W3587A/L3591D/F3603A, RyR2(ADA)) impairs inhibition of RyR2 by CaM and results in cardiac hypertrophy and early death of mice carrying the RyR2(ADA) mutation. To test the cellular function of CaMKII in cardiac hypertrophy, mutant mice were crossed with mice expressing the CaMKII inhibitory AC3-I peptide or the control AC3-C peptide in the myocardium. Inhibition of CaMKII by AC3-I modestly reduced CaMKII-dependent phosphorylation of RyR2 at Ser-2815 and markedly reduced CaMKII-dependent phosphorylation of SERCA2a regulatory subunit phospholamban at Thr-17. However the average life span and heart-to-body weight ratio of Ryr2(ADA/ADA) mice expressing the inhibitory peptide were not altered compared to control mice. In Ryr2(ADA/ADA) homozygous mice, AC3-I did not alter cardiac morphology, enhance cardiac function, improve sarcoplasmic reticulum Ca(2+) handling, or suppress the expression of genes implicated in cardiac remodeling. The results suggest that CaMKII was not required for the rapid development of cardiac hypertrophy in Ryr2(ADA/ADA) mice. |
format | Online Article Text |
id | pubmed-4122402 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-41224022014-08-12 Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor Chakraborty, Asima Pasek, Daniel A. Huang, Tai-Qin Gomez, Angela C. Yamaguchi, Naohiro Anderson, Mark E. Meissner, Gerhard PLoS One Research Article In cardiac muscle, the release of calcium ions from the sarcoplasmic reticulum through ryanodine receptor ion channels (RyR2s) leads to muscle contraction. RyR2 is negatively regulated by calmodulin (CaM) and by phosphorylation of Ca(2+)/CaM-dependent protein kinase II (CaMKII). Substitution of three amino acid residues in the CaM binding domain of RyR2 (RyR2-W3587A/L3591D/F3603A, RyR2(ADA)) impairs inhibition of RyR2 by CaM and results in cardiac hypertrophy and early death of mice carrying the RyR2(ADA) mutation. To test the cellular function of CaMKII in cardiac hypertrophy, mutant mice were crossed with mice expressing the CaMKII inhibitory AC3-I peptide or the control AC3-C peptide in the myocardium. Inhibition of CaMKII by AC3-I modestly reduced CaMKII-dependent phosphorylation of RyR2 at Ser-2815 and markedly reduced CaMKII-dependent phosphorylation of SERCA2a regulatory subunit phospholamban at Thr-17. However the average life span and heart-to-body weight ratio of Ryr2(ADA/ADA) mice expressing the inhibitory peptide were not altered compared to control mice. In Ryr2(ADA/ADA) homozygous mice, AC3-I did not alter cardiac morphology, enhance cardiac function, improve sarcoplasmic reticulum Ca(2+) handling, or suppress the expression of genes implicated in cardiac remodeling. The results suggest that CaMKII was not required for the rapid development of cardiac hypertrophy in Ryr2(ADA/ADA) mice. Public Library of Science 2014-08-05 /pmc/articles/PMC4122402/ /pubmed/25093823 http://dx.doi.org/10.1371/journal.pone.0104338 Text en © 2014 Chakraborty et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Chakraborty, Asima Pasek, Daniel A. Huang, Tai-Qin Gomez, Angela C. Yamaguchi, Naohiro Anderson, Mark E. Meissner, Gerhard Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor |
title | Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor |
title_full | Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor |
title_fullStr | Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor |
title_full_unstemmed | Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor |
title_short | Inhibition of CaMKII Does Not Attenuate Cardiac Hypertrophy in Mice with Dysfunctional Ryanodine Receptor |
title_sort | inhibition of camkii does not attenuate cardiac hypertrophy in mice with dysfunctional ryanodine receptor |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122402/ https://www.ncbi.nlm.nih.gov/pubmed/25093823 http://dx.doi.org/10.1371/journal.pone.0104338 |
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