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PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle
Open accessAbstract
The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation–contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are “leaky.” RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.
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Citations
Cited by
Energy metabolism in heart failure
Ventura‐Clapier, R., Garnier, A., & Veksler, V. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2003.055095 · Cited by 499
Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging
Andersson, D. C., Betzenhauser, M. J., Reiken, S., Meli, A. C., Umanskaya, A., Xie, W., Shiomi, T., Zalk, R., Lacampagne, A., & Marks, A. R. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.05.014 · Cited by 424
Role of β-Adrenoceptor Signaling in Skeletal Muscle: Implications for Muscle Wasting and Disease
Lynch, G. S., & Ryall, J. G. (2008) · Physiological Reviews · doi:10.1152/physrev.00028.2007 · Cited by 410
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-citationINTRACELLULAR CALCIUM RELEASE AND CARDIAC DISEASE
Wehrens, X. H. T., Lehnart, S. E., & Marks, A. R. (2005) · Annual Review of Physiology · doi:10.1146/annurev.physiol.67.040403.114521 · Cited by 355
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Metadata
- Authors
- Reiken, S., Lacampagne, A., Zhou, H., Kherani, A., Lehnart, S. E., Ward, C., Huang, F., Gaburjakova, M., Gaburjakova, J., Rosemblit, N., Warren, M. S., He, K.-L., Yi, G.-H., Wang, J., Burkhoff, D., Vassort, G., & Marks, A. R.
- Venue
- The Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2003-03-10
- Volume
- 160
- Issue
- 6
- Pages
- 919-928
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- OpenAlex
- W2115263783
- Cited by
- 245
- References
- 0
- FWCI
- 3.86
- Type
- journal article
- Language
- en
- Open access
- green
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- Reiken, S., Lacampagne, A., Zhou, H., Kherani, A., Lehnart, S. E., Ward, C., Huang, F., Gaburjakova, M., Gaburjakova, J., Rosemblit, N., Warren, M. S., He, K.-L., Yi, G.-H., Wang, J., Burkhoff, D., Vassort, G., & Marks, A. R. (2003). PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle. The Journal of Cell Biology. https://doi.org/10.1083/jcb.200211012
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