Malignant hyperthermia is a pharmacogenetic clinical syndrome that manifests as a hypermetabolic crisis when a susceptible individual is exposed to an anesthetic triggering agent (Litman and Rosenberg, 2005). The excessive release of Calcium ions from the sarcoplasmic reticulum increases the frequency action potential of muscles, making them contract more and eventually eliminate the relaxation phase. As a result, muscle rigidity will occur. As muscles work harder, more carbon dioxide will be released into the bloodstream. When carbon dioxide is dissociated with water in the blood, carbonic acid will form which decrease the blood pH. Highly acidic environment will denature enzymes and other proteins that are needed to maintain a normal healthy life. According to Litman and Rosenberg (2005), the abnormally increase release of calcium is often caused by an inherited mutation in the gene for the ryanodine receptor (RyR1) that resides in the membrane of the sarcoplasmic reticulum. If the disease isn’t treated properly, muscles will eventually exhaust and become dysfunctional; thus, muscle tissue is broken down, and contents are released into blood (rhabdomyolysis). In the worst case, death can occur as uncontrolled hypermetabolism leads to cellular hypoxia (Rosenberg et al., 2007).
PKA-mediated phosphorylation decreases the binding affinity of RyR2 for FKBP12.6, thus increasing the open probability of the channel and amplifying its response to calcium-dependent activation (Marx et al.,2000). Further studies on this disease were conducted by Professor Van Petegem’s research team. Phosphomimetic at S2813 leads to structural changes and enhanced affinity for PKA which increase its activity (Ghassemi et al., 2019). Their results show that RyR1 phosphorylation domain is a poor PKA substrate while RyR2 phosphorylation domain is an excellent PKA substrate (Ghassemi et al., 2019). The correlation of different types of RyRs and PKA is better understanding which is important for further investigation to be conducted by other scientists.
References:
Litman, R. S. Malignant Hyperthermia : Update on Susceptibility Testing. JAMA 2005, 293 (23), 2918–2924. https://doi.org/10.1001/jama.293.23.2918
Malignant hyperthermia - Symptoms and causes https://www.mayoclinic.org/diseases-conditions/malignant-hyperthermia/symptoms-causes/syc-20353750 (accessed Jan 6, 2020).
Rosenberg, H.; Davis, M.; James, D.; Pollock, N.; Stowell, K. Malignant Hyperthermia. Orphanet journal of rare diseases 2007, 2, 21. https://doi.org/10.1186/1750-1172-2-21
Priori, S. G.; Napolitano, C. Cardiac and Skeletal Muscle Disorders Caused by Mutations in the Intracellular Ca2+ Release Channels. The Journal of clinical investigation 2005, 115 (8), 2033–2038. https://doi.org/10.1172/JCI25664
Steven O Marx; Steven Reiken; Yuji Hisamatsu; Thotalla Jayaraman; Daniel Burkhoff; Nora Rosemblit; Andrew R Marks. PKA Phosphorylation Dissociates FKBP12.6 from the Calcium Release Channel (Ryanodine Receptor): Defective Regulation in Failing Hearts. 2000, 101 (4), 365–376. https://doi.org/10.1016/S0092-8674(00)80847-8
Omid Haji-Ghassemi; Zhiguang Yuchi; Filip Van Petegem. The Cardiac Ryanodine Receptor Phosphorylation Hotspot Embraces PKA in a Phosphorylation-Dependent Manner. Molecular Cell 2019, 75 (1), 39-52.e4. https://doi.org/10.1016/j.molcel.2019.04.019
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