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Article

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

Division of Pharmacology, Department of Neuroscience, School of Medicine, Federico II University of Naples, Naples, Italy

Abstract

I. Introduction

II. Molecular Biology of Na+/Ca2+ Exchanger

III. Brain Distribution of Na+/Ca2+ Exchanger Isoforms

A. Cerebral Cortex

B. Hippocampus

C. Mesencephalon and Basal Ganglia

D. Cerebellum

E. Median Eminence

IV. Regulation of Na+/Ca2+ Exchanger Activity

A. Intracellular Ca2+ Concentrations

B. Intracellular Na+ Concentrations

C. Intracellular H+ Concentrations

D. ATP, Protein Kinase A, Protein Kinase C, and Phosphatidylinositol 4,5 Bisphosphate

E. Phosphoarginine

F. Redox Agents

G. Gaseous Mediator: NO

V. Pharmacological Modulation of Na+/Ca2+ Exchanger Activity

VI. Inhibitors

A. Inorganic Cations

B. Organic Derivatives

1. Peptides.

C. Heterocycles

D. Antisense Oligodeoxynucleotides versus Na+/Ca2+ Exchanger Isoforms

VII. Activators

A. Inorganic Cations

B. Redox Agents

C. Organic Compounds

VIII. Na+/Ca2+ Exchanger Intervention in Physiological Conditions

A. Na+/Ca2+ Exchanger: Hormonal and Neurotransmitter Release

B. Effect of Knocking Out Na+/Ca2+ Exchanger Genes

IX. Relevance of Na+/Ca2+ Exchanger Activity in Pathophysiological Conditions

A. Hypoxia-Anoxia

B. White Matter Degeneration after Spinal Cord Injury, Brain Trauma, and Optical Nerve Injury

C. Na+/Ca2+ Exchanger and Neuronal Apoptosis

D. Aging

E. Alzheimer's Disease

X. Conclusions and Future Perspectives

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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