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).

• Authors: Karin Jurkat-Rott, Marc-André Weber, Michael Fauler, Xiu-Hai Guo, Boris D Holzherr, Agathe Paczulla, Nikolai Nordsborg, Wolfgang Joechle, Frank Lehmann-Horn
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 10 Pg. 4036-41 (Mar 10 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19225109 (Publication Type: Journal Article)

Chemical References

• Cations
• DNA, Complementary
• Ion Channels
• Potassium Channels, Inwardly Rectifying
• Sodium
• Sodium-Potassium-Exchanging ATPase
• Potassium

Topics

• Adult
• Aged, 80 and over
• Animals
• Cations
• DNA, Complementary (genetics)
• Female
• Humans
• Hypokalemic Periodic Paralysis (physiopathology)
• In Vitro Techniques
• Intracellular Space (drug effects, metabolism)
• Ion Channel Gating (drug effects)
• Ion Channels (metabolism)
• Magnetic Resonance Imaging
• Male
• Membrane Potentials (drug effects)
• Middle Aged
• Muscle Weakness (physiopathology)
• Potassium (pharmacology)
• Potassium Channels, Inwardly Rectifying (metabolism)
• Rats
• Reverse Transcriptase Polymerase Chain Reaction
• Sodium (metabolism)
• Sodium-Potassium-Exchanging ATPase (genetics, metabolism)