Sodium-calcium exchanger

The sodium-calcium exchanger (often denoted

maintenance of Ca2+ concentration in the endoplas+
2+
Na /Ca exchanger, NCX, or exchange protein) is
mic reticulum of both excitable and nonexcitable
an antiporter membrane protein that removes calcium
cells
from cells. It uses the energy that is stored in the
excitation-contraction coupling
electrochemical gradient of sodium (Na+ ) by allowing
+
Na to ow down its gradient across the plasma mem maintenance of low Ca2+ concentration in the mitobrane in exchange for the countertransport of calcium
chondria
ions (Ca2+ ). The NCX removes a single calcium ion in
exchange for the import of three sodium ions.[1] The
exchanger exists in many dierent cell types and animal The exchanger is also implicated in the cardiac electrical
species.[2] The NCX is considered one of the most conduction abnormality known as delayed afterdepolarization.[7] It is thought that intracellular accumulation of
important cellular mechanisms for removing Ca2+ .[2]
Ca2+ causes the activation of the Na+ /Ca2+ exchanger.
The exchanger is usually found in the plasma membranes
The result is a brief inux of a net positive charge (reand the mitochondria and endoplasmic reticulum of exmember 3 Na+ in, 1 Ca2+ out), thereby causing cellular
citable cells.[3][4]
depolarization.[7] This abnormal cellular depolarization
can lead to a cardiac arrhythmia.

Function
2 Reversibility

The Na+ /Ca2+ exchanger does not bind very tightly to

Ca2+ (has a low anity), but it can transport the ions
rapidly (has a high capacity), transporting up to ve thousand Ca2+ ions per second.[5] Therefore, it requires large
concentrations of Ca2+ to be eective, 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 cells 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 anity but a much lower capacity.
Since the PMCA is capable of eectively 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.

Since the transport is electrogenic (alters the membrane potential), depolarization of the membrane can reverse the exchangers 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 dierent areas of the cell, depending on the combined
eects of Na+ and Ca2+ gradients.[1]

The exchanger is involved in a variety of cell functions 2.1

including the following:[2]
control of neurosecretion
activity of photoreceptor cells
cardiac muscle relaxation
maintenance of Ca2+ concentration
sarcoplasmic reticulum in cardiac cells

in

Na+ /Ca2+ exchanger in the cardiac action potential

The ability for the Na+ /Ca2+ exchanger to reverse direction of ow 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 exthe tracellular Na+ concentration gradient to help pump Ca2+
out of the cell.[10] In fact, the Na+ /Ca2+ exchanger is in the
1

Ca2+ eux position most of the time. However, during

the upstroke of the cardiac action potential there is a large
inux 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 inux of
Ca2+ through the L-type calcium channel, and the exchanger returns to its forward direction of ow, pumping
Ca2+ out of the cell.[10]
While the exchanger normally works in the Ca2+ eux
position (with the exception of early in the action potential), certain conditions can abnormally switch the exchanger to the reverse (Ca2+ inux, Na+ eux) 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+ inux channels are inhibited.
If the action potential duration is prolonged.

History

[2] Dipolo, R; Beaug, L (2006). Sodium/calcium exchanger: Inuence of metabolic regulation on ion carrier interactions. Physiological Reviews 86 (1): 155203.
doi:10.1152/physrev.00018.2005. PMID 16371597.
[3] Kiedrowski, L; Brooker, G; Costa, E; Wroblewski, JT
(1994). Glutamate impairs neuronal calcium extrusion while reducing sodium gradient. Neuron 12 (2):
295300. 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+ Buering. 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): 107260. doi:10.1080/20014091074183.
PMID 11370791.
[6] Siegel, GJ; Agrano, 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] 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.

In 1968, H Reuter and N Seitz published ndings that,

when Na+ is removed from the medium surrounding a [9]
cell, the eux 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 nding that
proposed that there exists a means of Na+ exit from cells
[10]
other than the sodium-potassium pump.[2][12]

See also
Active transport
Cardiac action potential
Potassium-dependent sodium-calcium exchanger

EXTERNAL LINKS

Wolf, JA; Stys, PK; Lusardi, T; Meaney, D; Smith, DH

(2001). Traumatic Axonal Injury Induces Calcium Inux Modulated by Tetrodotoxin-Sensitive Sodium Channels. Journal of Neuroscience 21 (6): 192330. PMID
11245677.
Bers, Donald (2002).
Cardiac excitation
contraction coupling. Nature 415 (6868): 198205.
doi:10.1038/415198a. PMID 11805843.

[11] Reuter H, Seitz N (March 1968). The dependence of

calcium eux from cardiac muscle on temperature and
external ion composition. J. Physiol. (Lond.) 195 (2):
45170. PMC 1351672. PMID 5647333.
[12] Baker PF, Blaustein MP, Hodgkin AL, Steinhardt RA
(February 1969). The inuence of calcium on sodium
eux in squid axons. J. Physiol. (Lond.) 200 (2): 431
58. PMC 1350476. PMID 5764407.

References

[1] Yu, SP; Choi, DW (1997). Na+ Ca2+ exchange currents in cortical neurons: concomitant forward and reverse operation and eect of glutamate. European Journal of Neuroscience 9 (6): 127381. doi:10.1111/j.14609568.1997.tb01482.x. PMID 9215711.

6 External links
Sodium-calcium exchanger at the US National
Library of Medicine Medical Subject Headings
(MeSH)

3
Diagram at cvphysiology.com
Klabunde, RE. 2007. Cardiovascular Physiology
Concepts: Calcium Exchange.

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