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

doi:10.1073/pnas.0811277106

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

123 Citations (Scopus)

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).

Original language	English
Journal	Proceedings of the National Academy of Science of the United States of America
Volume	106
Issue number	10
Pages (from-to)	4036-4041
Number of pages	6
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.0811277106
Publication status	Published - 2009

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10.1073/pnas.0811277106

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Jurkat-Rott, K., Weber, M.-A., Fauler, M., Guo, X.-H., Holzherr, B. D., Paczulla, A., Nordsborg, N., Joechle, W., & Lehmann-Horn, F. (2009). K⁺-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. Proceedings of the National Academy of Science of the United States of America, 106(10), 4036-4041. https://doi.org/10.1073/pnas.0811277106

K⁺-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks. / Jurkat-Rott, Karin; Weber, Marc-André; Fauler, Michael et al.
In: Proceedings of the National Academy of Science of the United States of America, Vol. 106, No. 10, 2009, p. 4036-4041.

Research output: Contribution to journal › Journal article › Research › peer-review

Jurkat-Rott, K, Weber, M-A, Fauler, M, Guo, X-H, Holzherr, BD, Paczulla, A, Nordsborg, N, Joechle, W & Lehmann-Horn, F 2009, 'K⁺-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks', Proceedings of the National Academy of Science of the United States of America, vol. 106, no. 10, pp. 4036-4041. https://doi.org/10.1073/pnas.0811277106

@article{f9459f70204711de9f0a000ea68e967b,

title = "K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks",

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).",

author = "Karin Jurkat-Rott and Marc-Andr{\'e} Weber and Michael Fauler and Xiu-Hai Guo and Holzherr, {Boris D.} and Agathe Paczulla and Nikolai Nordsborg and Wolfgang Joechle and Frank Lehmann-Horn",

note = "Keywords: Adult; Aged, 80 and over; Animals; Cations; DNA, Complementary; Female; Humans; Hypokalemic Periodic Paralysis; Intracellular Space; Ion Channel Gating; Ion Channels; Magnetic Resonance Imaging; Male; Membrane Potentials; Middle Aged; Muscle Weakness; Potassium; Potassium Channels, Inwardly Rectifying; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Sodium-Potassium-Exchanging ATPase",

year = "2009",

doi = "10.1073/pnas.0811277106",

language = "English",

volume = "106",

pages = "4036--4041",

journal = "Proceedings of the National Academy of Science of the United States of America",

issn = "0027-8424",

publisher = "The National Academy of Sciences of the United States of America",

number = "10",

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TY - JOUR

T1 - K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks

AU - Jurkat-Rott, Karin

AU - Weber, Marc-André

AU - Fauler, Michael

AU - Guo, Xiu-Hai

AU - Holzherr, Boris D.

AU - Paczulla, Agathe

AU - Nordsborg, Nikolai

AU - Joechle, Wolfgang

AU - Lehmann-Horn, Frank

N1 - Keywords: Adult; Aged, 80 and over; Animals; Cations; DNA, Complementary; Female; Humans; Hypokalemic Periodic Paralysis; Intracellular Space; Ion Channel Gating; Ion Channels; Magnetic Resonance Imaging; Male; Membrane Potentials; Middle Aged; Muscle Weakness; Potassium; Potassium Channels, Inwardly Rectifying; Rats; Reverse Transcriptase Polymerase Chain Reaction; Sodium; Sodium-Potassium-Exchanging ATPase

PY - 2009

Y1 - 2009

N2 - 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).

AB - 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).

U2 - 10.1073/pnas.0811277106

DO - 10.1073/pnas.0811277106

M3 - Journal article

C2 - 19225109

SN - 0027-8424

VL - 106

SP - 4036

EP - 4041

JO - Proceedings of the National Academy of Science of the United States of America

JF - Proceedings of the National Academy of Science of the United States of America

IS - 10

ER -

K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks

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K⁺-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks