Zhu Mengyuan, Sun Haijian, Cao Lei, Wu Zhiyuan, Leng Bin, Bian Jinsong
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, Guangdong, China.
J Mol Med (Berl). 2022 Mar;100(3):395-410. doi: 10.1007/s00109-021-02143-6. Epub 2021 Nov 27.
Na/K-ATPase (NKA) is a large transmembrane protein expressed in all cells. It is well studied for its ion exchanging function, which is indispensable for the maintenance of electrochemical gradients across the plasma membrane and herein neuronal excitability. The widely recognized pump function of NKA closely depends on its unique structure features and conformational changes upon binding of specific ions. Various Na-dependent secondary transport systems are rigorously controlled by the ionic gradients generated by NKA and are essential for multiple physiological processes. In addition, roles of NKA as a signal transducer have also been unveiled nowadays. Plethora of signaling cascades are defined including Src-Ras-MAPK signaling, IP3R-mediated calcium oscillation, inflammation, and autophagy though most underlying mechanisms remain elusive. Ischemic stroke occurs when the blood flow carrying nutrients and oxygen into the brain is disrupted by blood clots, which is manifested by excitotoxicity, oxidative stress, inflammation, etc. The protective effect of NKA against ischemic stress is emerging gradually with the application of specific NKA inhibitor. However, NKA-related research is limited due to the opposite effects caused by NKA inhibitor at lower doses. The present review focuses on the recent progression involving different aspects about NKA in cellular homeostasis to present an in-depth understanding of this unique protein. Moreover, essential roles of NKA in ischemic pathology are discussed to provide a platform and bright future for the improvement in clinical research on ischemic stroke.
钠钾-ATP酶（NKA）是一种在所有细胞中都有表达的大型跨膜蛋白。其离子交换功能已得到充分研究，该功能对于维持跨质膜的电化学梯度以及神经元兴奋性而言不可或缺。NKA广为人知的泵功能紧密依赖于其独特的结构特征以及与特定离子结合时的构象变化。各种钠依赖性次级转运系统受到NKA产生的离子梯度的严格调控，并且对多种生理过程至关重要。此外，如今NKA作为信号转导器的作用也已被揭示。虽然大多数潜在机制仍不清楚，但已确定了大量的信号级联反应，包括Src-Ras-MAPK信号传导、IP3R介导的钙振荡、炎症和自噬。当携带营养物质和氧气进入大脑的血流被血凝块阻断时，就会发生缺血性中风，其表现为兴奋性毒性、氧化应激、炎症等。随着特异性NKA抑制剂的应用，NKA对缺血应激的保护作用正逐渐显现。然而，由于较低剂量的NKA抑制剂会产生相反的作用，与NKA相关的研究受到限制。本综述重点关注NKA在细胞稳态不同方面的最新进展，以深入了解这种独特的蛋白质。此外，还讨论了NKA在缺血性病理中的重要作用，为改善缺血性中风的临床研究提供一个平台和光明的未来。
