K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks
K+-dependent paradoxical membrane depolarization and Na+ overload, major and reversible contributors to weakness by ion channel leaks
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DOI：
10.1073/pnas.0811277106
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发表时间：
2009-03-10
影响因子：
11.1
通讯作者：
Lehmann-Horn, Frank
中科院分区：
文献类型：
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作者：
Jurkat-Rott, Karin;Weber, Marc-Andre;Lehmann-Horn, Frank
正常细胞外K+浓度([K+](O))为4 mM时，肌纤维的正常静息电位(P1)符合Nernst方程，约为-85 mV。超极化随着[K+](O)的降低而发生，尽管在[K+](O)和lt；1.0 mm处，肌纤维反常地去极化到第二稳定电位-60 mV(P2)。在大鼠的肌纤维束中，P2也存在于更具生理性的[K+](O)，并与不兴奋性有关。要将P2的相对频率提高到50%，需要将[K+](O)降低到1.5 mm。在离子载体ogicidin存在的情况下，将[K+](O)还原到仅2.5 mM也能产生同样的效果。乙酰唑胺使P2纤维的这种增加的频率正常化。这些发现模拟了低血钾性周期性麻痹(HypoPP)，这是一种以低钾引起的虚弱为特征的通道病。在7例HypoPP患者中，根据他们的永久性软弱，在[K+](O)为4 mm时，高达25%的肌纤维位于P2，根据他们的瘫痪发作，在[K+](O)为1.5 mm时，高达99%的肌纤维位于P2。在36例HypoPP患者中，25例表现为永久性无力和肌浆内Na+([Na+](I))超载(达24 mm)，体内Na-23-MRI显示。乙酰唑胺使[Na+](I)正常化，肌力增强。HypoPP肌纤维显示非选择性阳离子渗漏12-19.5亩S/厘米(2)，这可能是Na+超载的原因。泄漏使肌纤维对降低的血清K+敏感，由此产生的膜去极化导致肌纤维的虚弱。我们推测，在[K+](O)还原时，矛盾的去极化和功能丧失的原理也适用于其他组织，如心脏或脑，当它们变得漏水时(例如，由于缺血)。
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 1.5mM, 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 Na-23-MRI. Acetazolamide normalized [Na+](i) and increased muscle strength. HypoPP myofibers showed a nonselective cation leak of 12-19.5 mu S/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).