Annunziato L, Pignataro G, Di Renzo G F
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Via S. Pansini, 5-80131 Naples, Italy.
Pharmacol Rev. 2004 Dec;56(4):633-54. doi: 10.1124/pr.56.4.5.
In the last two decades, there has been a growing interest in unraveling the role that the Na+/Ca2+ exchanger (NCX) plays in the function and regulation of several cellular activities. Molecular biology, electrophysiology, genetically modified mice, and molecular pharmacology have helped to delve deeper and more successfully into the physiological and pathophysiological role of this exchanger. In fact, this nine-transmembrane protein, widely distributed in the brain and in the heart, works in a bidirectional way. Specifically, when it operates in the forward mode of operation, it couples the extrusion of one Ca2+ ion with the influx of three Na+ ions. In contrast, when it operates in the reverse mode of operation, while three Na+ ions are extruded, one Ca2+ enters into the cells. Different isoforms of NCX, named NCX1, NCX2, and NCX3, have been described in the brain, whereas only one, NCX1, has been found in the heart. The hypothesis that NCX can play a relevant role in several pathophysiological conditions, including hypoxia-anoxia, white matter degeneration after spinal cord injury, brain trauma and optical nerve injury, neuronal apoptosis, brain aging, and Alzheimer's disease, stems from the observation that NCX, in parallel with selective ion channels and ATP-dependent pumps, is efficient at maintaining intracellular Ca2+ and Na+ homeostasis. In conclusion, although studies concerning the involvement of NCX in the pathological mechanisms underlying brain injury during neurodegenerative diseases started later than those related to heart disease, the availability of pharmacological agents able to selectively modulate each NCX subtype activity and antiporter mode of operation will provide a better understanding of its pathophysiological role and, consequently, more promising approaches to treat these neurological disorders.
在过去二十年中，人们对阐明钠钙交换体（NCX）在多种细胞活动的功能和调节中所起的作用越来越感兴趣。分子生物学、电生理学、基因工程小鼠和分子药理学有助于更深入、更成功地探究这种交换体的生理和病理生理作用。事实上，这种广泛分布于大脑和心脏的九次跨膜蛋白以双向方式发挥作用。具体而言，当它以前向运作模式工作时，它将一个Ca2+离子的外流与三个Na+离子的内流相偶联。相反，当它以反向运作模式工作时，在三个Na+离子被排出的同时，一个Ca2+进入细胞。在大脑中已描述了NCX的不同亚型，即NCX1、NCX2和NCX3，而在心脏中仅发现了一种，即NCX1。NCX在包括缺氧 - 缺血、脊髓损伤后白质变性、脑外伤和视神经损伤、神经元凋亡、脑老化以及阿尔茨海默病在内的多种病理生理状况中可能发挥相关作用，这一假设源于以下观察结果：与选择性离子通道和ATP依赖性泵并行，NCX在维持细胞内Ca2+和Na+稳态方面效率很高。总之，尽管关于NCX参与神经退行性疾病期间脑损伤病理机制的研究比与心脏病相关的研究起步晚，但能够选择性调节每种NCX亚型活性和反向转运体运作模式的药物的出现，将有助于更好地理解其病理生理作用，从而为治疗这些神经疾病提供更有前景的方法。
