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# K⁺-Dependent Paradoxical Membrane Depolarization and Na⁺ Overload, Major and Reversible Contributors to Weakness by Ion Channel Leaks

Karin Jurkat-Rott, Marc-André Weber, Michael Fauler, Xiu-Hai Guo, Boris D. Holzherr, Agathe Paczulla, Nikolai Nordsborg, Wolfgang Joechle, Frank Lehmann-Horn and Erwin Neher
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 10 (Mar. 10, 2009), pp. 4036-4041
Stable URL: http://www.jstor.org/stable/40428495
Page Count: 6
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## Abstract

Normal resting potential (P1) of myofibers follows the Nernst equation, exhibiting about -85 mV at a normal extracellular K⁺ concentration ($\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$) of 4 mM. Hyperpolarization occurs with decreased $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$, although at $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ < 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 $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ and was associated with inexcitability. To increase the relative frequency of P2 to 50%, $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ needed to be lowered to 1.5 mM. In the presence of the ionophore gramicidin, $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ 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 $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ of 4 mM, in accordance with their permanent weakness, and up to 99% were in P2 at a $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ of 1.5 mM, in accordance with their paralytic attacks. Of 36 HypoPP patients, 25 had permanent weakness and myoplasmic intracellular Na⁺ ($\left[ {{\rm{Na}}^{\rm{ + }} } \right]_{\rm{i}}$) overload (up to 24 mM) as shown by in vivo ²³Na-MRI. Acetazolamide normalized $\left[ {{\rm{Na}}^{\rm{ + }} } \right]_{\rm{i}}$ and increased muscle strength. HypoPP myofibers showed a nonselective cation leak of 12-19.5 μS/cm², 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 $\left[ {{\rm{K}}^{\rm{ + }} } \right]_{\rm{o}}$ reduction may apply to other tissues, such as heart or brain, when they become leaky (e.g., because of ischemia).

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