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Encyclopedia of Molecular Pharmacology pp 1–11Cite as

Na+/Ca2+ Exchangers

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Synonyms

Na+/Ca2+ antiporter; Na+/Ca2+ exchanger; NCX; NCX1; NCX2; NCX3; Sodium calcium exchanger

Definition

The plasma membrane Na+/Ca2+ exchanger is a high-capacity and low-affinity ionic transporter that exchanges three Na+ ions for one Ca2+ ion. When intracellular Ca2+ concentrations ([Ca2+]i) rise and the cells require the return to resting levels, this exchanger couples the uphill extrusion of Ca2+ ions to the influx of Na+ ions into the cells down their electrochemical gradient. This mode of operation, defined as forward mode, or Ca2+ efflux mechanism, keeps the 104-fold difference in [Ca2+]i across the cell membrane. Under other physiological or pathophysiological conditions when the intracellular Na+ concentrations ([Na+]i) rise, or membrane depolarization occurs and reduces the transmembrane Na+ electrochemical gradient, the Na+/Ca2+ exchanger mediates the extrusion of Na+ and the influx of Ca2+ ions. This last mode of operation is defined as reverse mode or Ca2+influx...

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References

  • Annunziato L, Pignataro G, Di Renzo GF (2004) Pharmacology of brain Na+/Ca2+ exchanger: from molecular biology to therapeutic perspectives. Pharmacol Rev 56(4):633–654. 56/4/633 [pii]. https://doi.org/10.1124/pr.56.4.5

    Article  CAS  PubMed  Google Scholar 

  • Annunziato L, Pignataro G, Boscia F, Sirabella R, Formisano L, Saggese M, Cuomo O, Gala R, Secondo A, Viggiano D, Molinaro P, Valsecchi V, Tortiglione A, Adornetto A, Scorziello A, Cataldi M, Di Renzo GF (2007) ncx1, ncx2, and ncx3 gene product expression and function in neuronal anoxia and brain ischemia. Ann N Y Acad Sci 1099:413–426. https://doi.org/10.1196/annals.1387.050

    Article  CAS  PubMed  Google Scholar 

  • Boscia F, D’Avanzo C, Pannaccione A, Secondo A, Casamassa A, Formisano L, Guida N, Sokolow S, Herchuelz A, Annunziato L (2012) Silencing or knocking out the Na(+)/Ca(2+) exchanger-3 (NCX3) impairs oligodendrocyte differentiation. Cell Death Differ 19(4):562–572. https://doi.org/10.1038/cdd.2011.125

    Article  CAS  PubMed  Google Scholar 

  • Casamassa A, La Rocca C, Sokolow S, Herchuelz A, Matarese G, Annunziato L, Boscia F (2016) Ncx3 gene ablation impairs oligodendrocyte precursor response and increases susceptibility to experimental autoimmune encephalomyelitis. Glia 64(7):1124–1137. https://doi.org/10.1002/glia.22985

    Article  PubMed  Google Scholar 

  • Cerullo P, Brancaccio P, Anzilotti S, Vinciguerra A, Cuomo O, Fiorino F, Severino B, Di Vaio P, Di Renzo G, Annunziato L, Pignataro G (2018) Acute and long-term NCX activation reduces brain injury and restores behavioral functions in mice subjected to neonatal brain ischemia. Neuropharmacology 135:180–191. https://doi.org/10.1016/j.neuropharm.2018.03.017

    Article  CAS  PubMed  Google Scholar 

  • de Rosa V, Secondo A, Pannaccione A, Ciccone R, Formisano L, Guida N, Crispino R, Fico A, Polishchuk R, D'Aniello A, Annunziato L, Boscia F (2019) D-Aspartate treatment attenuates myelin damage and stimulates myelin repair. EMBO Mol Med 11(1). https://doi.org/10.15252/emmm.201809278

  • Hilge M, Aelen J, Vuister GW (2006) Ca2+ regulation in the Na+/Ca2+ exchanger involves two markedly different Ca2+ sensors. Mol Cell 22(1):15–25. S1097-2765(06)00169-9 [pii]. https://doi.org/10.1016/j.molcel.2006.03.008

    Article  CAS  PubMed  Google Scholar 

  • Iwamoto T (2004) Forefront of Na+/Ca2+ exchanger studies: molecular pharmacology of Na+/Ca2+ exchange inhibitors. J Pharmacol Sci 96(1):27–32. ST.JSTAGE/jphs/FMJ04002X6 [pii]

    Article  CAS  Google Scholar 

  • Jeon D, Yang YM, Jeong MJ, Philipson KD, Rhim H, Shin HS (2003) Enhanced learning and memory in mice lacking Na+/Ca2+ exchanger 2. Neuron 38(6):965–976

    Article  CAS  Google Scholar 

  • Linck B, Qiu Z, He Z, Tong Q, Hilgemann DW, Philipson KD (1998) Functional comparison of the three isoforms of the Na+/Ca2+ exchanger (NCX1, NCX2, NCX3). Am J Phys 274(2 Pt 1):C415–C423

    Article  CAS  Google Scholar 

  • Molinaro P, Cuomo O, Pignataro G, Boscia F, Sirabella R, Pannaccione A, Secondo A, Scorziello A, Adornetto A, Gala R, Viggiano D, Sokolow S, Herchuelz A, Schurmans S, Di Renzo G, Annunziato L (2008) Targeted disruption of Na+/Ca2+ exchanger 3 (NCX3) gene leads to a worsening of ischemic brain damage. J Neurosci 28(5):1179–1184. https://doi.org/10.1523/JNEUROSCI.4671-07.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molinaro P, Viggiano D, Nistico R, Sirabella R, Secondo A, Boscia F, Pannaccione A, Scorziello A, Mehdawy B, Sokolow S, Herchuelz A, Di Renzo GF, Annunziato L (2011) Na+-Ca2+ exchanger (NCX3) knock-out mice display an impairment in hippocampal long-term potentiation and spatial learning and memory. J Neurosci 31(20):7312–7321. https://doi.org/10.1523/JNEUROSCI.6296-10.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molinaro P, Cantile M, Cuomo O, Secondo A, Pannaccione A, Ambrosino P, Pignataro G, Fiorino F, Severino B, Gatta E, Sisalli MJ, Milanese M, Scorziello A, Bonanno G, Robello M, Santagada V, Caliendo G, Di Renzo G, Annunziato L (2013) Neurounina-1, a novel compound that increases Na+/Ca2+ exchanger activity, effectively protects against stroke damage. Mol Pharmacol 83(1):142–156. https://doi.org/10.1124/mol.112.080986

    Article  CAS  PubMed  Google Scholar 

  • Molinaro P, Pannaccione A, Sisalli MJ, Secondo A, Cuomo O, Sirabella R, Cantile M, Ciccone R, Scorziello A, di Renzo G, Annunziato L (2015) A new cell-penetrating peptide that blocks the autoinhibitory XIP domain of NCX1 and enhances antiporter activity. Mol Ther 23(3):465–476. https://doi.org/10.1038/mt.2014.231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Molinaro P, Sirabella R, Pignataro G, Petrozziello T, Secondo A, Boscia F, Vinciguerra A, Cuomo O, Philipson KD, De Felice M, Di Lauro R, Di Renzo G, Annunziato L (2016) Neuronal NCX1 overexpression induces stroke resistance while knockout induces vulnerability via Akt. J Cereb Blood Flow Metab 36(10):1790–1803. https://doi.org/10.1177/0271678X15611913

    Article  CAS  PubMed  Google Scholar 

  • Natale S, Anzilotti S, Petrozziello T, Ciccone R, Serani A, Calabrese L, Severino B, Frecentese F, Secondo A, Pannaccione A, Fiorino F, Cuomo O, Vinciguerra A, D’Esposito L, Sadile AG, Cabib S, Renzo GD, Annunziato L, Molinaro P (2020) Genetic Up-Regulation or Pharmacological Activation of the Na+/Ca2+ Exchanger 1 (NCX1) Enhances Hippocampal-Dependent Contextual and Spatial Learning and Memory. Molecular Neurobiology

    Google Scholar 

  • Ottolia M, Nicoll DA, Philipson KD (2009) Roles of two Ca2+-binding domains in regulation of the cardiac Na+-Ca2+ exchanger. J Biol Chem 284(47):32735–32741. M109.055434 [pii]. https://doi.org/10.1074/jbc.M109.055434

    Article  PubMed  PubMed Central  Google Scholar 

  • Pannaccione A, Secondo A, Molinaro P, D’Avanzo C, Cantile M, Esposito A, Boscia F, Scorziello A, Sirabella R, Sokolow S, Herchuelz A, Di Renzo G, Annunziato L (2012) A new concept: Abeta1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death. J Neurosci 32(31):10609–10617. https://doi.org/10.1523/JNEUROSCI.6429-11.2012.32/31/10609. [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Philipson KD, Nicoll DA (2000) Sodium-calcium exchange: a molecular perspective. Annu Rev Physiol 62:111–133. https://doi.org/10.1146/annurev.physiol.62.1.111

    Article  CAS  PubMed  Google Scholar 

  • Pignataro G, Gala R, Cuomo O, Tortiglione A, Giaccio L, Castaldo P, Sirabella R, Matrone C, Canitano A, Amoroso S, Di Renzo G, Annunziato L (2004) Two sodium/calcium exchanger gene products, NCX1 and NCX3, play a major role in the development of permanent focal cerebral ischemia. Stroke 35(11):2566–2570. 01.STR.0000143730.29964.93 [pii]. https://doi.org/10.1161/01.STR.0000143730.29964.93

    Article  CAS  PubMed  Google Scholar 

  • Ren X, Philipson KD (2013) The topology of the cardiac Na(+)/Ca(2+) exchanger, NCX1. J Mol Cell Cardiol 57:68–71. https://doi.org/10.1016/j.yjmcc.2013.01.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scorziello A, Savoia C, Sisalli MJ, Adornetto A, Secondo A, Boscia F, Esposito A, Polishchuk EV, Polishchuk RS, Molinaro P, Carlucci A, Lignitto L, Di Renzo G, Feliciello A, Annunziato L (2013) NCX3 regulates mitochondrial Ca(2+) handling through the AKAP121-anchored signaling complex and prevents hypoxia-induced neuronal death. J Cell Sci 126(Pt 24):5566–5577. https://doi.org/10.1242/jcs.129668

    Article  CAS  PubMed  Google Scholar 

  • Secondo A, Staiano RI, Scorziello A, Sirabella R, Boscia F, Adornetto A, Valsecchi V, Molinaro P, Canzoniero LM, Di Renzo G, Annunziato L (2007) BHK cells transfected with NCX3 are more resistant to hypoxia followed by reoxygenation than those transfected with NCX1 and NCX2: possible relationship with mitochondrial membrane potential. Cell Calcium 42(6):521–535. S0143-4160(07)00019-X [pii]. https://doi.org/10.1016/j.ceca.2007.01.006

    Article  CAS  PubMed  Google Scholar 

  • Secondo A, Esposito A, Petrozziello T, Boscia F, Molinaro P, Tedeschi V, Pannaccione A, Ciccone R, Guida N, Di Renzo G, Annunziato L (2018) Na(+)/Ca(2+) exchanger 1 on nuclear envelope controls PTEN/Akt pathway via nucleoplasmic Ca(2+) regulation during neuronal differentiation. Cell Death Discov 4:12. https://doi.org/10.1038/s41420-017-0018-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sirabella R, Secondo A, Pannaccione A, Scorziello A, Valsecchi V, Adornetto A, Bilo L, Di Renzo G, Annunziato L (2009) Anoxia-induced NF-kappaB-dependent upregulation of NCX1 contributes to Ca2+ refilling into endoplasmic reticulum in cortical neurons. Stroke 40(3):922–929. STROKEAHA.108.531962 [pii]. https://doi.org/10.1161/STROKEAHA.108.531962

    Article  CAS  PubMed  Google Scholar 

  • Sirabella R, Sisalli MJ, Costa G, Omura K, Ianniello G, Pinna A, Morelli M, Di Renzo GM, Annunziato L, Scorziello A (2018) NCX1 and NCX3 as potential factors contributing to neurodegeneration and neuroinflammation in the A53T transgenic mouse model of Parkinson’s disease. Cell Death Dis 9(7):725. https://doi.org/10.1038/s41419-018-0775-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sokolow S, Henkins KM, Bilousova T, Miller CA, Vinters HV, Poon W, Cole GM, Gylys KH (2011) AD synapses contain abundant Abeta monomer and multiple soluble oligomers, including a 56-kDa assembly. Neurobiol Aging. S0197-4580(11)00194-1 [pii]. https://doi.org/10.1016/j.neurobiolaging.2011.05.011

  • Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M, Riedel D, Urlaub H, Schenck S, Brugger B, Ringler P, Muller SA, Rammner B, Grater F, Hub JS, De Groot BL, Mieskes G, Moriyama Y, Klingauf J, Grubmuller H, Heuser J, Wieland F, Jahn R (2006) Molecular anatomy of a trafficking organelle. Cell 127(4):831–846. S0092-8674(06)01400-0 [pii]. https://doi.org/10.1016/j.cell.2006.10.030

    Article  CAS  PubMed  Google Scholar 

  • Vinciguerra A, Formisano L, Cerullo P, Guida N, Cuomo O, Esposito A, Di Renzo G, Annunziato L, Pignataro G (2014) MicroRNA-103-1 selectively downregulates brain NCX1 and its inhibition by anti-miRNA ameliorates stroke damage and neurological deficits. Mol Ther 22(10):1829–1838. https://doi.org/10.1038/mt.2014.113. S1525-0016(16)30786-9 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Pharmacology, Department of Neuroscience, School of Medicine, “Federico II” University of Naples, Naples, Italy

    Lucio Annunziato, Giuseppe Pignataro & Pasquale Molinaro

Authors
  1. Lucio Annunziato
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  2. Giuseppe Pignataro
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  3. Pasquale Molinaro
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Corresponding author

Correspondence to Lucio Annunziato .

Editor information

Editors and Affiliations

  1. Max-Planck-Institut Herz/Lungenforschg., Bad Nauheim, Hessen, Germany

    Stefan Offermanns

  2. Presidential Office, Friedrich-Schiller University Jena, Jena, Thüringen, Germany

    Walter Rosenthal

Glossary

CBD1 and CBD2

Calcium binding domain 1 and 2 of the f loop

f loop

Intracellular domain between transmembrane segments 5 and 6 of the sodium calcium exchanger

Forward or Ca2+ efflux mode

Mode of operation of NCX extruding calcium and intruding sodium ions

Na+-dependent Ca2+ uptake

Calcium uptake elicited by reduced concentrations of extracellular sodium

PIP2

Phosphatidylinositol 4,5 bisphosphate

Reverse or Ca2+ influx mode

Mode of operation of NCX extruding sodium and intruding calcium ions

XIP

20 amino acid region of the f loop of the sodium calcium exchanger

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Annunziato, L., Pignataro, G., Molinaro, P. (2020). Na+/Ca2+ Exchangers. In: Offermanns, S., Rosenthal, W. (eds) Encyclopedia of Molecular Pharmacology. Springer, Cham. https://doi.org/10.1007/978-3-030-21573-6_192-1

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  • DOI: https://doi.org/10.1007/978-3-030-21573-6_192-1

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  • Print ISBN: 978-3-030-21573-6

  • Online ISBN: 978-3-030-21573-6

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