ArticleProceedings of the National Academy of Sciences of the United States of America2009
K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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87 citing papers in PubMed, 167 citations in OpenAlex.
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- Mechanisms underlying the distinct K+ dependencies of periodic paralysis.The Journal of general physiology · 2025Article
- Potassium-sensitive loss of muscle force in the setting of reduced inward rectifier KProceedings of the National Academy of Sciences of the United States of America · 2025Article
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- Ion currents through the voltage sensor domain of distinct families of proteins.Journal of biological physics · 2023Review
- Hypokalemic periodic paralysis: a 3-year follow-up study.Journal of neurology · 2023Article
- Muscle channelopathies: A review.Annals of the Child Neurology Society · 2023Review
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- Voltage-dependent CaAmerican journal of physiology. Cell physiology · 2022Article
- Hypokalaemia with Guillain-Barré syndrome: a diagnostic and therapeutic challenge.BMJ case reports · 2022Article
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- Gating pore currents occur in CaV1.1 domain III mutants associated with HypoPP.The Journal of general physiology · 2021Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- New Challenges Resulting From the Loss of Function of NaFrontiers in pharmacology · 2021Review
- Skeletal muscle CaPflugers Archiv : European journal of physiology · 2020Review
- Increases in [IP3]i aggravates diastolic [Ca2+] and contractile dysfunction in Chagas' human cardiomyocytes.PLoS neglected tropical diseases · 2020Article
- Toward Decoding Bioelectric Events in Xenopus Embryogenesis: New Methodology for Tracking Interplay Between Calcium and Resting Potentials In Vivo.Journal of molecular biology · 2020Article
27 more citing papers are in PubMed but not listed here.
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9 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Normal resting potential (P1) of myofibers follows the Nernst equation, exhibiting about -85 mV at a normal extracellular K(+) concentration ([K(+)](o)) of 4 mM. Hyperpolarization occurs with decreased [K(+)](o), although at [K(+)](o) < 1.0 mM, myofibers paradoxically depolarize to a second stable potential of -60 mV (P2). In rat myofiber bundles, P2 also was found at more physiological [K(+)](o) and was associated with inexcitability. To increase the relative frequency of P2 to 50%, [K(+)](o) needed to be lowered to 1.5 mM. In the presence of the ionophore gramicidin, [K(+)](o) reduction to only 2.5 mM yielded the same effect. Acetazolamide normalized this increased frequency of P2 fibers. The findings mimic hypokalemic periodic paralysis (HypoPP), a channelopathy characterized by hypokalemia-induced weakness. Of myofibers from 7 HypoPP patients, up to 25% were in P2 at a [K(+)](o) of 4 mM, in accordance with their permanent weakness, and up to 99% were in P2 at a [K(+)](o) of 1.5 mM, in accordance with their paralytic attacks. Of 36 HypoPP patients, 25 had permanent weakness and myoplasmic intracellular Na(+) ([Na(+)](i)) overload (up to 24 mM) as shown by in vivo (23)Na-MRI. Acetazolamide normalized [Na(+)](i) and increased muscle strength. HypoPP myofibers showed a nonselective cation leak of 12-19.5 microS/cm(2), which may explain the Na(+) overload. The leak sensitizes myofibers to reduced serum K(+), and the resulting membrane depolarization causes the weakness. We postulate that the principle of paradoxical depolarization and loss of function upon [K(+)](o) reduction may apply to other tissues, such as heart or brain, when they become leaky (e.g., because of ischemia).
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