Bogdanova A, Grenacher B, Nikinmaa M, Gassmann M
Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.
J Exp Biol. 2005 May;208(Pt 10):1793-801. doi: 10.1242/jeb.01572.
Reduction in oxygenation induces inhibition of Na+/K+ ATPase in a number of cells and tissues, including hepatocytes. When not reversed, decrease in Na+/K+ pump activity leads to a gradual Na+ accumulation, cell swelling and death. However, when accompanied by suppression of dissipative cation pathways, it has also been shown to be a beneficial adaptive strategy used by some hypoxia-tolerant species to reduce ATP consumption during prolonged periods of anoxia. This study aims to investigate acute hypoxic responses of the Na+/K+ ATPase in primary cultures of trout hepatocytes. Gradual decrease in oxygenation was followed by an instantaneous transient dose-dependent downregulation of the Na+/K+ ATPase transport activity, but was without an effect on hydrolytic function of the enzyme. Hypoxia-induced inhibition of active K+ influx was reversed spontaneously when hypoxic incubation time exceeded 20 min. The stimulating effect of prolonged hypoxic exposure on the Na+/K+ pump is most probably secondary to hypoxia-induced activation of the Na+/H+ exchanger with the following Na+ accumulation leading to Na+/K+ ATPase activation. Hypoxia-induced inhibition of the Na+/K+ pump was not caused by ATP depletion or global oxidative stress. However, local controlled production of reactive oxygen species seems to play an important role in hypoxia-induced regulation of the Na+/K+ ATPase. Treatment of cells with mercaptopropionyl glycine (MPG), a scavenger of OH*-, abolished hypoxia-induced inhibition of the Na+/K+ ATPase. Earlier on we have shown that activation of Na+/H+ exchanger under hypoxic conditions can be opposed by MPG treatment as well. Taken together our results suggest that regulation of both oxygen-sensitive transporters may be accomplished by local changes in free radical production.
氧合作用降低会在包括肝细胞在内的许多细胞和组织中诱导钠钾ATP酶的抑制。当这种抑制未得到逆转时，钠钾泵活性的降低会导致钠逐渐积累、细胞肿胀和死亡。然而，当伴有耗散性阳离子途径的抑制时，这也被证明是一些耐缺氧物种在长时间缺氧期间减少ATP消耗所采用的一种有益的适应性策略。本研究旨在调查鳟鱼肝细胞原代培养物中钠钾ATP酶的急性缺氧反应。氧合作用逐渐降低后，钠钾ATP酶的转运活性会立即出现瞬时剂量依赖性下调，但对该酶的水解功能没有影响。当缺氧孵育时间超过20分钟时，缺氧诱导的活性钾内流抑制会自发逆转。长时间缺氧暴露对钠钾泵的刺激作用很可能继发于缺氧诱导的钠氢交换体激活，随后钠积累导致钠钾ATP酶激活。缺氧诱导的钠钾泵抑制不是由ATP耗竭或全身性氧化应激引起的。然而，局部受控产生的活性氧似乎在缺氧诱导的钠钾ATP酶调节中起重要作用。用巯基丙酰甘氨酸（MPG）（一种羟基自由基清除剂）处理细胞可消除缺氧诱导的钠钾ATP酶抑制。此前我们还表明，MPG处理也可以对抗缺氧条件下钠氢交换体的激活。综上所述，我们的结果表明，这两种氧敏感转运体的调节可能通过自由基产生的局部变化来实现。
