Department of Neurology
Cellular and Molecular Physiology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Musculoskeletal Diseases | Musculoskeletal System | Nervous System Diseases | Neurology
Hyperkalemic periodic paralysis (HyperKPP) manifests as stiffness or subclinical myotonic discharges before or during periods of episodic muscle weakness or paralysis. Ingestion of Ca2+ alleviates HyperKPP symptoms, but the mechanism is unknown because lowering extracellular [Ca2+] ([Ca2+]e) has no effect on force development in normal muscles under normal conditions. Lowering [Ca2+]e, however, is known to increase the inactivation of voltage-gated cation channels, especially when the membrane is depolarized. Two hypotheses were tested: (1) lowering [Ca2+]e depresses force in normal muscles under conditions that depolarize the cell membrane; and (2) HyperKPP muscles have a greater sensitivity to low Ca2+-induced force depression because many fibers are depolarized, even at a normal [K+]e. In wild type muscles, lowering [Ca2+]e from 2.4 to 0.3 mM had little effect on tetanic force and membrane excitability at a normal K+ concentration of 4.7 mM, whereas it significantly enhanced K+-induced depression of force and membrane excitability. In HyperKPP muscles, lowering [Ca2+]e enhanced the K+-induced loss of force and membrane excitability not only at elevated [K+]e but also at 4.7 mM K+. Lowering [Ca2+]e increased the incidence of generating fast and transient contractures and gave rise to a slower increase in unstimulated force, especially in HyperKPP muscles. Lowering [Ca2+]e reduced the efficacy of salbutamol, a beta2 adrenergic receptor agonist and a treatment for HyperKPP, to increase force at elevated [K+]e. Replacing Ca2+ by an equivalent concentration of Mg2+ neither fully nor consistently reverses the effects of lowering [Ca2+]e. These results suggest that the greater Ca2+ sensitivity of HyperKPP muscles primarily relates to (1) a greater effect of Ca2+ in depolarized fibers and (2) an increased proportion of depolarized HyperKPP muscle fibers compared with control muscle fibers, even at normal [K+]e.
Cellular Physiology, Contraction and Cell Motility
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DOI of Published Version
Uwera F, Ammar T, McRae C, Hayward LJ, Renaud JM. Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles. J Gen Physiol. 2020 Jul 6;152(7):e201912511. doi: 10.1085/jgp.201912511. PMID: 32291438. Link to article on publisher's site
The Journal of general physiology
Uwera F, Ammar T, McRae C, Hayward LJ, Renaud J. (2020). Lower Ca2+ enhances the K+-induced force depression in normal and HyperKPP mouse muscles. Neurology Publications. https://doi.org/10.1085/jgp.201912511. Retrieved from https://escholarship.umassmed.edu/neuro_pp/457
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This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 4.0 License.
Available for download on Wednesday, January 06, 2021
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