Abstract
The Na+-Ca2+ exchanger (NCX) is critical for Ca2+ homeostasis throughout the body. Of the three isoforms in the NCX family, NCX1 has been extensively studied, providing a good basis for understanding the molecular aspects of the NCX family, including structural resemblances, stoichiometry, and mechanism of exchange. However, the tissue expression of the third isoform of the family, NCX3, together with its proposed involvement in the Ca2+ fluxes of the endoplasmic reticulum and the mitochondria suggests a distinctive role for this isoform. Investigations of the exchanger revealed the involvement of NCX3 in diverse processes such as bone formation, TNF-α production, slow-twitch muscle contraction, and long-term potentiation in the hippocampus. Furthermore, the study of its posttranslational modification, its cleavage by the Ca2+-sensitive protease, calpain, and its upregulation in numerous stress conditions linked NCX3 to the aberrant Ca2+ influx seen during neuronal excitotoxicity in Alzheimer’s disease, brain stroke, and neuronal injuries. Hence, beyond its role in calcium homeostasis, NCX3 plays an important role in stress conditions, neuronal excitotoxicity, and metabolism and is thereby a key element in many cell types. The present review aims to survey the knowledge on NCX3, focusing on the recent discoveries on its functional and structural properties, and discusses the implications of NCX3 in both physiological and pathological conditions.
Keywords
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Abbreviations
- AD:
-
Alzheimer’s disease
- Aβ1–42 :
-
Amyloid peptide 1–42
- CBD:
-
Calcium-binding domain
- CLD:
-
Catenin-like domain
- DMD:
-
Duchenne muscular dystrophy
- ER:
-
Endoplasmic reticulum
- FDB:
-
Flexor digitorum brevis
- ICC:
-
Interstitial cell of Cajal
- LGMD2A:
-
Limb-girdle muscular dystrophy 2A
- LTP:
-
Long-term potentiation
- NCX:
-
Na+-Ca2+ exchanger
- NMJ:
-
Neuromuscular junction
- PIP2 :
-
Phosphatidylinositol-4,5-phosphate
- PKA:
-
Protein kinase A
- PKC:
-
Protein kinase C
- SOCE:
-
Store-operated Ca2+ entry
- SR:
-
Sarcoplasmic reticulum
- TNF-α:
-
Tumor necrosis factor-alpha
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This work was performed in the Centre for Systems Biology Research Initiative and financed by the grant CSBR09/013 V from the Netherlands Organization for Scientific Research.
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Michel, L.Y.M., Hoenderop, J.G.J., Bindels, R.J.M. (2015). Towards Understanding the Role of the Na+-Ca2+ Exchanger Isoform 3. In: Nilius, B., Gudermann, T., Jahn, R., Lill, R., Petersen, O., de Tombe, P. (eds) Reviews of Physiology, Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 168. Springer, Cham. https://doi.org/10.1007/112_2015_23
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