Towards Understanding the Role of the Na+-Ca2+ Exchanger Isoform 3

  • Lauriane Y. M. MichelEmail author
  • Joost G. J. Hoenderop
  • René J. M. Bindels
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 168)


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.


Alternative splicing Ca2+ Calpain Endoplasmic reticulum Neuronal excitotxicity Skeletal muscle Sodium–Calcium exchanger Transport 



Alzheimer’s disease


Amyloid peptide 1–42


Calcium-binding domain


Catenin-like domain


Duchenne muscular dystrophy


Endoplasmic reticulum


Flexor digitorum brevis


Interstitial cell of Cajal


Limb-girdle muscular dystrophy 2A


Long-term potentiation


Na+-Ca2+ exchanger


Neuromuscular junction




Protein kinase A


Protein kinase C


Store-operated Ca2+ entry


Sarcoplasmic reticulum


Tumor necrosis factor-alpha



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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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Lauriane Y. M. Michel
    • 1
    Email author
  • Joost G. J. Hoenderop
    • 1
  • René J. M. Bindels
    • 1
  1. 1.Department of Physiology, Radboud Institute for Molecular Life SciencesRadboud University Medical CenterNijmegenThe Netherlands

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