Sodium-calcium exchanger

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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]


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[edit]

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.


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][11] 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][12]

See also[edit]


  1. ^ a b c d e f Yu, SP; Choi, DW (1997). "Na+–Ca2+ exchange currents in cortical neurons: concomitant forward and reverse operation and effect of glutamate". European Journal of Neuroscience 9 (6): 1273–81. doi:10.1111/j.1460-9568.1997.tb01482.x. PMID 9215711. 
  2. ^ a b c d e Dipolo, R; Beaugé, L (2006). "Sodium/calcium exchanger: Influence of metabolic regulation on ion carrier interactions". Physiological Reviews 86 (1): 155–203. doi:10.1152/physrev.00018.2005. PMID 16371597. 
  3. ^ a b Kiedrowski, L; Brooker, G; Costa, E; Wroblewski, JT (1994). "Glutamate impairs neuronal calcium extrusion while reducing sodium gradient". Neuron 12 (2): 295–300. doi:10.1016/0896-6273(94)90272-0. PMID 7906528. 
  4. ^ Patterson M, Sneyd J, Friel DD (January 2007). "Depolarization-induced Calcium Responses in Sympathetic Neurons: Relative Contributions from Ca2+ Entry, Extrusion, ER/Mitochondrial Ca2+ Uptake and Release, and Ca2+ Buffering". J. Gen. Physiol. 129 (1): 29–56. doi:10.1085/jgp.200609660. PMC 2151609. PMID 17190902. 
  5. ^ Carafoli, E; Santella, L; Branca, D; Brini, M. (2001). "Generation, control, and processing of cellular calcium signals". Critical Reviews in Biochemistry and Molecular Biology 36 (2): 107–260. doi:10.1080/20014091074183. PMID 11370791. 
  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. ISBN 0-7817-0104-X. 
  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 (1995). "Excitotoxic degeneration is initiated at non-random sites in cultured rat cerebellar neurons". Journal of Neuroscience 15 (11): 6999–7011. PMID 7472456. 
  9. ^ Wolf, JA; Stys, PK; Lusardi, T; Meaney, D; Smith, DH (2001). "Traumatic Axonal Injury Induces Calcium Influx Modulated by Tetrodotoxin-Sensitive Sodium Channels". Journal of Neuroscience 21 (6): 1923–30. PMID 11245677. 
  10. ^ a b c d Bers, Donald (2002). "Cardiac excitation–contraction coupling". Nature 415 (6868): 198–205. doi:10.1038/415198a. PMID 11805843. 
  11. ^ Reuter H, Seitz N (March 1968). "The dependence of calcium efflux from cardiac muscle on temperature and external ion composition". J. Physiol. (Lond.) 195 (2): 451–70. PMC 1351672. PMID 5647333. 
  12. ^ Baker PF, Blaustein MP, Hodgkin AL, Steinhardt RA (February 1969). "The influence of calcium on sodium efflux in squid axons". J. Physiol. (Lond.) 200 (2): 431–58. PMC 1350476. PMID 5764407. 

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