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

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Reviews of Physiology, Biochemistry and Pharmacology

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 168))

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.

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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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Acknowledgments

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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Authors and Affiliations

  1. Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Lauriane Y. M. Michel, Joost G. J. Hoenderop & René J. M. Bindels

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  1. Lauriane Y. M. Michel
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  2. Joost G. J. Hoenderop
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  3. René J. M. Bindels
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Correspondence to Lauriane Y. M. Michel .

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Editors and Affiliations

  1. KU Leuven, Leuven, Belgium

    Bernd Nilius

  2. Klinikum der Universität München Abteilung, München, Bayern, Germany

    Thomas Gudermann

  3. Max-Planck-Inst for Biophysical Chemistr, Göttingen, Niedersachsen, Germany

    Reinhard Jahn

  4. University of Marburg, Marburg, Hessen, Germany

    Roland Lill

  5. Cardiff School of Biosciences, Cardiff University, Cardiff, United Kingdom

    Ole H. Petersen

  6. Dept. of Cell and Molec. Physiology, Loyola University Chicago, MAYWOOD, Illinois, USA

    Pieter P. de Tombe

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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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