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Research ArticleArticle

Pharmacology of Brain Na+/Ca2+ Exchanger: From Molecular Biology to Therapeutic Perspectives

L. Annunziato, G. Pignataro and G. F. Di Renzo
Pharmacological Reviews December 2004, 56 (4) 633-654; DOI: https://doi.org/10.1124/pr.56.4.5
L. Annunziato
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy
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G. Pignataro
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy
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G. F. Di Renzo
Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy
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Abstract

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.

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Pharmacological Reviews: 56 (4)
Pharmacological Reviews
Vol. 56, Issue 4
1 Dec 2004
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Research ArticleArticle

Pharmacology of Brain Na+/Ca2+ Exchanger: From Molecular Biology to Therapeutic Perspectives

L. Annunziato, G. Pignataro and G. F. Di Renzo
Pharmacological Reviews December 1, 2004, 56 (4) 633-654; DOI: https://doi.org/10.1124/pr.56.4.5

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Research ArticleArticle

Pharmacology of Brain Na+/Ca2+ Exchanger: From Molecular Biology to Therapeutic Perspectives

L. Annunziato, G. Pignataro and G. F. Di Renzo
Pharmacological Reviews December 1, 2004, 56 (4) 633-654; DOI: https://doi.org/10.1124/pr.56.4.5
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  • Article
    • Abstract
    • I. Introduction
    • II. Molecular Biology of Na+/Ca2+ Exchanger
    • III. Brain Distribution of Na+/Ca2+ Exchanger Isoforms
    • IV. Regulation of Na+/Ca2+ Exchanger Activity
    • V. Pharmacological Modulation of Na+/Ca2+ Exchanger Activity
    • VI. Inhibitors
    • VII. Activators
    • VIII. Na+/Ca2+ Exchanger Intervention in Physiological Conditions
    • IX. Relevance of Na+/Ca2+ Exchanger Activity in Pathophysiological Conditions
    • X. Conclusions and Future Perspectives
    • Acknowledgments
    • Footnotes
    • References
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