Bogdanova Anna, Petrushanko Irina Y, Hernansanz-Agustín Pablo, Martínez-Ruiz Antonio
Institute of Veterinary Physiology, Vetsuisse Faculty and the Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich Zurich, Switzerland.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences Moscow, Russia.
Front Physiol. 2016 Aug 2;7:314. doi: 10.3389/fphys.2016.00314. eCollection 2016.
Control over the Na,K-ATPase function plays a central role in adaptation of the organisms to hypoxic and anoxic conditions. As the enzyme itself does not possess O2 binding sites its "oxygen-sensitivity" is mediated by a variety of redox-sensitive modifications including S-glutathionylation, S-nitrosylation, and redox-sensitive phosphorylation. This is an overview of the current knowledge on the plethora of molecular mechanisms tuning the activity of the ATP-consuming Na,K-ATPase to the cellular metabolic activity. Recent findings suggest that oxygen-derived free radicals and H2O2, NO, and oxidized glutathione are the signaling messengers that make the Na,K-ATPase "oxygen-sensitive." This very ancient signaling pathway targeting thiols of all three subunits of the Na,K-ATPase as well as redox-sensitive kinases sustains the enzyme activity at the "optimal" level avoiding terminal ATP depletion and maintaining the transmembrane ion gradients in cells of anoxia-tolerant species. We acknowledge the complexity of the underlying processes as we characterize the sources of reactive oxygen and nitrogen species production in hypoxic cells, and identify their targets, the reactive thiol groups which, upon modification, impact the enzyme activity. Structured accordingly, this review presents a summary on (i) the sources of free radical production in hypoxic cells, (ii) localization of regulatory thiols within the Na,K-ATPase and the role reversible thiol modifications play in responses of the enzyme to a variety of stimuli (hypoxia, receptors' activation) (iii) redox-sensitive regulatory phosphorylation, and (iv) the role of fine modulation of the Na,K-ATPase function in survival success under hypoxic conditions. The co-authors attempted to cover all the contradictions and standing hypotheses in the field and propose the possible future developments in this dynamic area of research, the importance of which is hard to overestimate. Better understanding of the processes underlying successful adaptation strategies will make it possible to harness them and use for treatment of patients with stroke and myocardial infarction, sleep apnoea and high altitude pulmonary oedema, and those undergoing surgical interventions associated with the interruption of blood perfusion.
对钠钾-ATP酶功能的控制在生物体适应缺氧和无氧条件中起着核心作用。由于该酶本身不具备氧气结合位点，其“氧敏感性”是由多种氧化还原敏感修饰介导的，包括S-谷胱甘肽化、S-亚硝基化和氧化还原敏感的磷酸化。本文概述了目前关于大量分子机制的知识，这些机制将消耗ATP的钠钾-ATP酶的活性调节至细胞代谢活性水平。最近的研究结果表明，氧衍生的自由基、过氧化氢、一氧化氮和氧化型谷胱甘肽是使钠钾-ATP酶具有“氧敏感性”的信号信使。这条非常古老的信号通路靶向钠钾-ATP酶所有三个亚基的硫醇以及氧化还原敏感激酶，将酶活性维持在“最佳”水平，避免ATP最终耗尽，并维持耐缺氧物种细胞中的跨膜离子梯度。在描述缺氧细胞中活性氧和氮物种产生的来源，并确定其靶点（即反应性硫醇基团，修饰后会影响酶活性）时，我们认识到潜在过程的复杂性。基于此结构，本综述总结了以下内容：（i）缺氧细胞中自由基产生的来源；（ii）钠钾-ATP酶内调节性硫醇的定位以及可逆硫醇修饰在酶对各种刺激（缺氧、受体激活）反应中所起的作用；（iii）氧化还原敏感的调节性磷酸化；（iv）钠钾-ATP酶功能的精细调节在缺氧条件下生存成功中的作用。共同作者试图涵盖该领域所有的矛盾和现存假说，并提出这一动态研究领域可能的未来发展方向，其重要性无论怎样高估都不为过。更好地理解成功适应策略背后的过程将有可能利用它们来治疗中风、心肌梗死、睡眠呼吸暂停和高原肺水肿患者，以及那些接受与血液灌注中断相关手术干预的患者。
