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Sodium-calcium exchanger

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Title: Sodium-calcium exchanger  
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Subject: Solute carrier family, Antiporter, Gelsolin, SLC2A13, SLC2A14
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Sodium-calcium exchanger

solute carrier family 8 (sodium/calcium exchanger), member 1
Symbol SLC8A1
Alt. symbols NCX1
Entrez 6546
HUGO 11068
OMIM 182305
RefSeq NM_021097
UniProt P32418
Other data
Locus Chr. 2 p23-p21
solute carrier family 8 (sodium-calcium exchanger), member 2
Symbol SLC8A2
Entrez 6543
HUGO 11069
OMIM 601901
RefSeq NM_015063
UniProt Q9UPR5
Other data
Locus Chr. 19 q13.2
solute carrier family 8 (sodium-calcium exchanger), member 3
Symbol SLC8A3
Entrez 6547
HUGO 11070
OMIM 607991
RefSeq NM_033262
UniProt P57103
Other data
Locus Chr. 14 q24.1

The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, NCX, or exchange protein) is an antiporter membrane protein that removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). The NCX removes a single calcium ion in exchange for the import of three sodium ions.[1] The exchanger exists in many different cell types and animal species.[2] The NCX is considered one of the most important cellular mechanisms for removing Ca2+.[2]

The exchanger is usually found in the plasma membranes and the mitochondria and endoplasmic reticulum of excitable cells.[3][4]


  • Function 1
  • Reversibility 2
    • Na+/Ca2+ exchanger in the cardiac action potential 2.1
  • Structure 3
  • History 4
  • See also 5
  • References 6
  • External links 7


The Na+/Ca2+ exchanger does not bind very tightly to Ca2+ (has a low affinity), but it can transport the ions rapidly (has a high capacity), transporting up to five thousand Ca2+ ions per second.[5] Therefore, it requires large concentrations of Ca2+ to be effective, but is useful for ridding the cell of large amounts of Ca2+ in a short time, as is needed in a neuron after an action potential. Thus, the exchanger also likely plays an important role in regaining the cell's normal calcium concentrations after an excitotoxic insult.[3] Another, more ubiquitous transmembrane pump that exports calcium from the cell is the plasma membrane Ca2+ ATPase (PMCA), which has a much higher affinity but a much lower capacity. Since the PMCA is capable of effectively binding to Ca2+ even when its concentrations are quite low, it is better suited to the task of maintaining the very low concentrations of calcium that are normally within a cell.[6] Therefore the activities of the NCX and the PMCA complement each other.

The exchanger is involved in a variety of cell functions including the following:[2]

The exchanger is also implicated in the cardiac electrical conduction abnormality known as delayed afterdepolarization.[7] It is thought that intracellular accumulation of Ca2+ causes the activation of the Na+/Ca2+ exchanger. The result is a brief influx of a net positive charge (remember 3 Na+ in, 1 Ca2+ out), thereby causing cellular depolarization.[7] This abnormal cellular depolarization can lead to a cardiac arrhythmia.


Since the transport is electrogenic (alters the membrane potential), depolarization of the membrane can reverse the exchanger's direction if the cell is depolarized enough, as may occur in excitotoxicity.[1] In addition, as with other transport proteins, the amount and direction of transport depends on transmembrane substrate gradients.[1] This fact can be protective because increases in intracellular Ca2+ concentration that occur in excitotoxicity may activate the exchanger in the forward direction even in the presence of a lowered extracellular Na+ concentration.[1] However, it also means that, when intracellular levels of Na+ rise beyond a critical point, the NCX begins importing Ca2+.[1][8][9] The NCX may operate in both forward and reverse directions simultaneously in different areas of the cell, depending on the combined effects of Na+ and Ca2+ gradients.[1]

Na+/Ca2+ exchanger in the cardiac action potential

The ability for the Na+/Ca2+ exchanger to reverse direction of flow manifests itself during the cardiac action potential. Due to the delicate role that Ca2+ plays in the contraction of heart muscles, the cellular concentration of Ca2+ is carefully controlled. During the resting potential, the Na+/Ca2+ exchanger takes advantage of the large extracellular Na+ concentration gradient to help pump Ca2+ out of the cell.[10] In fact, the Na+/Ca2+ exchanger is in the Ca2+ efflux position most of the time. However, during the upstroke of the cardiac action potential there is a large influx of Na+ ions. This depolarizes the cell and shifts the membrane potential in the positive direction. What results is a large increase in intracellular [Na+]. This causes the reversal of the Na+/Ca2+ exchanger to pump Na+ ions out of the cell and Ca2+ ions into the cell.[10] However, this reversal of the exchanger lasts only momentarily due to the internal rise in [Ca2+] as a result of the influx of Ca2+ through the L-type calcium channel, and the exchanger returns to its forward direction of flow, pumping Ca2+ out of the cell.[10]

While the exchanger normally works in the Ca2+ efflux position (with the exception of early in the action potential), certain conditions can abnormally switch the exchanger to the reverse (Ca2+ influx, Na+ efflux) position. Listed below are several cellular and pharmaceutical conditions in which this happens.[10]

  • The internal [Na+] is higher than usual (like it is when digitalis glycoside medications block the Na+/K+ -ATPase pump.)
  • The Sarcoplasmic Reticulum release of Ca2+ is inhibited.
  • Other Ca2+ influx channels are inhibited.
  • If the action potential duration is prolonged.


Based on secondary structure and hydrophobicity predictions, NCX was initially predicted to have 9 transmembrane helices.[11] The family is believed to have arisen from a gene duplication event, due to apparent pseudo-symmetry within the primary sequence of the transmembrane domain.[12] Inserted between the pseudo-symmetric halves is a cytoplasmic loop containing regulatory domains.[13] These regulatory domains have C2 domain like structures and are responsible for calcium regulation.[14][15] Recently, the structure of an archaeal NCX ortholog has been solved by X-ray crystallography.[16] This clearly illustrates a dimeric transporter of 10 transmembrane helices, with a diamond shaped site for substrate binding. Based on the structure and structural symmetry, a model for alternating access with ion competition at the active site was proposed. The structures of three related proton-calcium exhangers (CAX) have been solved from yeast and bacteria. While structurally and functionally homologus, these structures illustrate novel oligomeric structures, substrate coupling, and regulation.[17][18][19]


In 1968, H Reuter and N Seitz published findings that, when Na+ is removed from the medium surrounding a cell, the efflux of Ca2+ is inhibited, and they proposed that there might be a mechanism for exchanging the two ions.[2][20] In 1969, a group led by PF Baker that was experimenting using squid axons published a finding that proposed that there exists a means of Na+ exit from cells other than the sodium-potassium pump.[2][21]

See also


  1. ^ a b c d e f Yu SP, Choi DW (Jun 1997). "Na(+)-Ca2+ exchange currents in cortical neurons: concomitant forward and reverse operation and effect of glutamate". The European Journal of Neuroscience 9 (6): 1273–81.  
  2. ^ a b c d e DiPolo R, Beaugé L (Jan 2006). "Sodium/calcium exchanger: influence of metabolic regulation on ion carrier interactions". Physiological Reviews 86 (1): 155–203.  
  3. ^ a b Kiedrowski L, Brooker G, Costa E, Wroblewski JT (Feb 1994). "Glutamate impairs neuronal calcium extrusion while reducing sodium gradient". Neuron 12 (2): 295–300.  
  4. ^ Patterson M, Sneyd J, Friel DD (Jan 2007). "Depolarization-induced calcium responses in sympathetic neurons: relative contributions from Ca2+ entry, extrusion, ER/mitochondrial Ca2+ uptake and release, and Ca2+ buffering". The Journal of General Physiology 129 (1): 29–56.  
  5. ^ Carafoli E, Santella L, Branca D, Brini M (Apr 2001). "Generation, control, and processing of cellular calcium signals". Critical Reviews in Biochemistry and Molecular Biology 36 (2): 107–260.  
  6. ^ Siegel, GJ; Agranoff, BW; Albers, RW; Fisher, SK; Uhler, MD, editors (1999). Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (6th ed.). Philadelphia: Lippincott,Williams & Wilkins.  
  7. ^ a b Lilly, L: "Pathophysiology of Heart Disease", chapter 11: "Mechanisms of Cardiac Arrhythmias", Lippencott, Williams and Wilkens, 2007
  8. ^ Bindokas VP, Miller RJ (Nov 1995). "Excitotoxic degeneration is initiated at non-random sites in cultured rat cerebellar neurons". The Journal of Neuroscience 15 (11): 6999–7011.  
  9. ^ Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH (Mar 2001). "Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels". The Journal of Neuroscience 21 (6): 1923–30.  
  10. ^ a b c d Bers DM (Jan 2002). "Cardiac excitation-contraction coupling". Nature 415 (6868): 198–205.  
  11. ^ Nicoll DA, Ottolia M, Philipson KD (Nov 2002). "Toward a topological model of the NCX1 exchanger". Annals of the New York Academy of Sciences 976: 11–8.  
  12. ^ Cai X, Lytton J (Sep 2004). "The cation/Ca(2+) exchanger superfamily: phylogenetic analysis and structural implications". Molecular Biology and Evolution 21 (9): 1692–703.  
  13. ^ Matsuoka S, Nicoll DA, Reilly RF, Hilgemann DW, Philipson KD (May 1993). "Initial localization of regulatory regions of the cardiac sarcolemmal Na(+)-Ca2+ exchanger". Proceedings of the National Academy of Sciences of the United States of America 90 (9): 3870–4.  
  14. ^ Besserer GM, Ottolia M, Nicoll DA, Chaptal V, Cascio D, Philipson KD, Abramson J (Nov 2007). "The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis". Proceedings of the National Academy of Sciences of the United States of America 104 (47): 18467–72.  
  15. ^ Nicoll DA, Sawaya MR, Kwon S, Cascio D, Philipson KD, Abramson J (Aug 2006). "The crystal structure of the primary Ca2+ sensor of the Na+/Ca2+ exchanger reveals a novel Ca2+ binding motif". The Journal of Biological Chemistry 281 (31): 21577–81.  
  16. ^ Liao J, Li H, Zeng W, Sauer DB, Belmares R, Jiang Y (Feb 2012). "Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger". Science 335 (6069): 686–90.  
  17. ^ Waight AB, Pedersen BP, Schlessinger A, Bonomi M, Chau BH, Roe-Zurz Z, Risenmay AJ, Sali A, Stroud RM (Jul 2013). "Structural basis for alternating access of a eukaryotic calcium/proton exchanger". Nature 499 (7456): 107–10.  
  18. ^ Nishizawa T, Kita S, Maturana AD, Furuya N, Hirata K, Kasuya G, Ogasawara S, Dohmae N, Iwamoto T, Ishitani R, Nureki O (Jul 2013). "Structural basis for the counter-transport mechanism of a H+/Ca2+ exchanger". Science 341 (6142): 168–72.  
  19. ^ Wu M, Tong S, Waltersperger S, Diederichs K, Wang M, Zheng L (Jul 2013). "Crystal structure of Ca2+/H+ antiporter protein YfkE reveals the mechanisms of Ca2+ efflux and its pH regulation". Proceedings of the National Academy of Sciences of the United States of America 110 (28): 11367–72.  
  20. ^ Reuter H, Seitz N (Mar 1968). "The dependence of calcium efflux from cardiac muscle on temperature and external ion composition". The Journal of Physiology 195 (2): 451–70.  
  21. ^ Baker PF, Blaustein MP, Hodgkin AL, Steinhardt RA (Feb 1969). "The influence of calcium on sodium efflux in squid axons". The Journal of Physiology 200 (2): 431–58.  

External links

  • Sodium-calcium exchanger at the US National Library of Medicine Medical Subject Headings (MeSH)
  • Diagram at
  • Klabunde, RE. 2007. Cardiovascular Physiology Concepts: Calcium Exchange.
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