K + -dependent paradoxical membrane depolarization and Na + overload, major and reversible contributors to weakness by ion channel leaks
| Autor: | Nikolai Baastrup Nordsborg, Wolfgang Joechle, Agathe Paczulla, Boris D. Holzherr, Frank Lehmann-Horn, Xiu-Hai Guo, Marc-André Weber, Michael Fauler, Karin Jurkat-Rott |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Adult
Male DNA Complementary Hypokalemic Periodic Paralysis Intracellular Space In Vitro Techniques Ion Channels Membrane Potentials chemistry.chemical_compound Nuclear magnetic resonance Channelopathy Hypokalemic periodic paralysis Cations medicine Animals Humans Potassium Channels Inwardly Rectifying Aged 80 and over Membrane potential Muscle Weakness Multidisciplinary Reverse Transcriptase Polymerase Chain Reaction Sodium Skeletal muscle Muscle weakness Depolarization Middle Aged Biological Sciences medicine.disease Magnetic Resonance Imaging Potassium channel Rats medicine.anatomical_structure chemistry Biochemistry Potassium Gramicidin Female Sodium-Potassium-Exchanging ATPase medicine.symptom Ion Channel Gating |
| Zdroj: | Proceedings of the National Academy of Sciences. 106:4036-4041 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0811277106 |
| Popis: | 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 μS/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). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|