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Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression
Open accessAbstract
Defective regulation of the cardiac ryanodine receptor (RyR2)/calcium release channel, required for excitation-contraction coupling in the heart, has been linked to cardiac arrhythmias and heart failure. For example, diastolic calcium “leak” via RyR2 channels in the sarcoplasmic reticulum has been identified as an important factor contributing to impaired contractility in heart failure and ventricular arrhythmias that cause sudden cardiac death. In patients with heart failure, chronic activation of the “fight or flight” stress response leads to protein kinase A (PKA) hyperphosphorylation of RyR2 at Ser-2808. PKA phosphorylation of RyR2 Ser-2808 reduces the binding affinity of the channel-stabilizing subunit calstabin2, resulting in leaky RyR2 channels. We developed RyR2-S2808A mice to determine whether Ser-2808 is the functional PKA phosphorylation site on RyR2. Furthermore, mice in which the RyR2 channel cannot be PKA phosphorylated were relatively protected against the development of heart failure after myocardial infarction. Taken together, these data show that PKA phosphorylation of Ser-2808 on the RyR2 channel appears to be a critical mediator of progressive cardiac dysfunction after myocardial infarction.
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Citations
Cited by
Left Cardiac Sympathetic Denervation for Catecholaminergic Polymorphic Ventricular Tachycardia
Wilde, A. A. M., Bhuiyan, Z. A., Crotti, L., Facchini, M., De Ferrari, G. M., Paul, T., Ferrandi, C., Koolbergen, D. R., Odero, A., & Schwartz, P. J. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0708006 · Cited by 432
Modulation of the Ryanodine Receptor and Intracellular Calcium
Zalk, R., Lehnart, S. E., & Marks, A. R. (2007) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.76.053105.094237 · Cited by 371
Self-citationMinding the calcium store: Ryanodine receptor activation as a convergent mechanism of PCB toxicity
Pessah, I. N., Cherednichenko, G., & Lein, P. J. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2009.10.009 · Cited by 231
Gorski, P. A., Ceholski, D. K., & Hajjar, R. J. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2015.01.005 · Cited by 213
Park, S.-J., Zhang, D., Qi, Y., Li, Y., Lee, K. Y., Bezzerides, V. J., Yang, P., Xia, S., Kim, S. L., Liu, X., et al. (2019) · Circulation · doi:10.1161/circulationaha.119.039711 · Cited by 140
Metadata
- Authors
- Wehrens, X. H. T., Lehnart, S. E., Reiken, S., Vest, J. A., Wronska, A., & Marks, A. R.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2006-01-06
- Volume
- 103
- Issue
- 3
- Pages
- 511-518
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2147343486
- Cited by
- 367
- References
- 0
- FWCI
- 15.97
- Type
- journal article
- Language
- en
- Open access
- green
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- Wehrens, X. H. T., Lehnart, S. E., Reiken, S., Vest, J. A., Wronska, A., & Marks, A. R. (2006). Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0510113103
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