View source for Sodium-calcium exchanger

{{infobox protein
| Name = solute carrier family 8 (sodium/calcium exchanger), member 1
| caption =
| image =
| width =
| HGNCid = 11068
| Symbol = SLC8A1
| AltSymbols = NCX1
| EntrezGene = 6546
| OMIM = 182305
| RefSeq = NM_021097
| UniProt = P32418
| PDB =
| ECnumber =
| Chromosome = 2
| Arm = p
| Band = 23
| LocusSupplementaryData = -p21
}}
{{infobox protein
| Name = solute carrier family 8 (sodium-calcium exchanger), member 2
| caption =
| image =
| width =
| HGNCid = 11069
| Symbol = SLC8A2
| AltSymbols =
| EntrezGene = 6543
| OMIM = 601901
| RefSeq = NM_015063
| UniProt = Q9UPR5
| PDB =
| ECnumber =
| Chromosome = 19
| Arm = q
| Band = 13.2
| LocusSupplementaryData =
}}
{{infobox protein
| Name = solute carrier family 8 (sodium-calcium exchanger), member 3
| caption =
| image =
| width =
| HGNCid = 11070
| Symbol = SLC8A3
| AltSymbols =
| EntrezGene = 6547
| OMIM = 607991
| RefSeq = NM_033262
| UniProt = P57103
| PDB =
| ECnumber =
| Chromosome = 14
| Arm = q
| Band = 24.1
| LocusSupplementaryData =
}}
The '''sodium-calcium exchanger''' (often denoted '''Na<sup>+</sup>/Ca<sup>2+</sup> 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<sup>+</sup>) by allowing Na<sup>+</sup> to flow down its gradient across the [[plasma membrane]] in exchange for the countertransport of [[calcium in biology|calcium]] ions (Ca<sup>2+</sup>). A single calcium ion is exported for the import of three sodium ions.<ref name="yuchoi">{{cite journal | vauthors = Yu SP, Choi DW | title = Na(+)-Ca2+ exchange currents in cortical neurons: concomitant forward and reverse operation and effect of glutamate | journal = The European Journal of Neuroscience | volume = 9 | issue = 6 | pages = 1273–81 | date = Jun 1997 | pmid = 9215711 | doi = 10.1111/j.1460-9568.1997.tb01482.x }}</ref> The exchanger exists in many different cell types and animal species.<ref name="Dipolo">{{cite journal | vauthors = DiPolo R, Beaugé L | title = Sodium/calcium exchanger: influence of metabolic regulation on ion carrier interactions | journal = Physiological Reviews | volume = 86 | issue = 1 | pages = 155–203 | date = Jan 2006 | pmid = 16371597 | doi = 10.1152/physrev.00018.2005 | url = http://physrev.physiology.org/cgi/content/abstract/86/1/155 }}</ref> The NCX is considered one of the most important cellular mechanisms for removing Ca<sup>2+</sup>.<ref name="Dipolo"/>

The exchanger is usually found in the plasma membranes and the mitochondria and [[endoplasmic reticulum]] of excitable cells.<ref name="Kiedrowski">{{cite journal | vauthors = Kiedrowski L, Brooker G, Costa E, Wroblewski JT | title = Glutamate impairs neuronal calcium extrusion while reducing sodium gradient | journal = Neuron | volume = 12 | issue = 2 | pages = 295–300 | date = Feb 1994 | pmid = 7906528 | doi = 10.1016/0896-6273(94)90272-0 }}</ref><ref>{{cite journal | vauthors = Patterson M, Sneyd J, Friel DD | title = Depolarization-induced calcium responses in sympathetic neurons: relative contributions from Ca2+ entry, extrusion, ER/mitochondrial Ca2+ uptake and release, and Ca2+ buffering | journal = The Journal of General Physiology | volume = 129 | issue = 1 | pages = 29–56 | date = Jan 2007 | pmid = 17190902 | pmc = 2151609 | doi = 10.1085/jgp.200609660 }}</ref>

== Function ==
The Na<sup>+</sup>/Ca<sup>2+</sup> exchanger does not bind very tightly to Ca<sup>2+</sup> (has a low affinity), but it can transport the [[ion]]s rapidly (has a high capacity), transporting up to five thousand Ca<sup>2+</sup> ions per second.<ref name="carafoli">{{cite journal | vauthors = Carafoli E, Santella L, Branca D, Brini M | title = Generation, control, and processing of cellular calcium signals | journal = Critical Reviews in Biochemistry and Molecular Biology | volume = 36 | issue = 2 | pages = 107–260 | date = Apr 2001 | pmid = 11370791 | doi = 10.1080/20014091074183 }}</ref> Therefore, it requires large concentrations of Ca<sup>2+</sup> to be effective, but is useful for ridding the cell of large amounts of Ca<sup>2+</sup> 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 [[excitotoxicity|excitotoxic]] insult.<ref name="Kiedrowski"/> Another, more ubiquitous [[transmembrane pump]] that exports calcium from the [[cell (biology)|cell]] is the [[plasma membrane Ca2+ ATPase|plasma membrane Ca<sup>2+</sup> ATPase]] (PMCA), which has a much higher affinity but a much lower capacity. Since the PMCA is capable of effectively binding to Ca<sup>2+</sup> 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.<ref name="Siegel">{{cite book | last=Siegel | first = GJ |author2=Agranoff, BW |author3=Albers, RW |author4=Fisher, SK |author5= Uhler, MD, editors  | title=Basic Neurochemistry: Molecular, Cellular, and Medical Aspects |edition=6th | publisher=Lippincott,Williams & Wilkins | year = 1999| location=Philadelphia | url=https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search&db=books&doptcmdl=GenBookHL&term=PMCA+AND+bnchm%5Bbook%5D+AND+160156%5Buid%5D&rid=bnchm.section.344#345 | isbn=0-7817-0104-X }}</ref> 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:<ref name="Dipolo"/>
*control of [[neurosecretion]]
*activity of [[photoreceptor cell]]s
*[[Cardiac excitation-contraction coupling|cardiac muscle relaxation]]
*maintenance of Ca<sup>2+</sup> concentration in the [[sarcoplasmic reticulum]] in cardiac cells
*maintenance of Ca<sup>2+</sup> concentration in the endoplasmic reticulum of both excitable and nonexcitable cells
*[[excitation-contraction coupling]]
*maintenance of low Ca<sup>2+</sup> concentration in the mitochondria

The exchanger is also implicated in the cardiac electrical conduction abnormality known as [[afterdepolarization|delayed afterdepolarization]].<ref name="Lilly">Lilly, L: "Pathophysiology of Heart Disease", chapter 11: "Mechanisms of Cardiac Arrhythmias", Lippencott, Williams and Wilkens, 2007</ref> It is thought that intracellular accumulation of Ca<sup>2+</sup> causes the activation of the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger. The result is a brief influx of a net positive charge (remember 3 Na<sup>+</sup> in, 1 Ca<sup>2+</sup> out), thereby causing cellular depolarization.<ref name="Lilly"/> This abnormal cellular depolarization can lead to a cardiac arrhythmia.

==Reversibility==
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]].<ref name="yuchoi"/> In addition, as with other transport proteins, the amount and direction of transport depends on transmembrane substrate gradients.<ref name="yuchoi"/> This fact can be protective because increases in intracellular Ca<sup>2+</sup> concentration that occur in excitotoxicity may activate the exchanger in the forward direction even in the presence of a lowered extracellular Na<sup>+</sup> concentration.<ref name="yuchoi"/> However, it also means that, when intracellular levels of Na<sup>+</sup> rise beyond a critical point, the NCX begins importing Ca<sup>2+</sup>.<ref name="yuchoi"/><ref>{{cite journal | vauthors = Bindokas VP, Miller RJ | title = Excitotoxic degeneration is initiated at non-random sites in cultured rat cerebellar neurons | journal = The Journal of Neuroscience | volume = 15 | issue = 11 | pages = 6999–7011 | date = Nov 1995 | pmid = 7472456 | url = http://www.jneurosci.org/cgi/reprint/15/11/6999 }}</ref><ref>{{cite journal | vauthors = Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH | title = Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels | journal = The Journal of Neuroscience | volume = 21 | issue = 6 | pages = 1923–30 | date = Mar 2001 | pmid = 11245677 | url = http://www.jneurosci.org/cgi/content/full/21/6/1923 }}</ref> The NCX may operate in both forward and reverse directions simultaneously in different areas of the cell, depending on the combined effects of Na<sup>+</sup> and Ca<sup>2+</sup> gradients.<ref name="yuchoi"/> This effect may prolong calcium transients following bursts of neuronal activity, thus influencing neuronal information processing.<ref>{{Cite journal|last=Zylbertal|first=Asaph|last2=Kahan|first2=Anat|last3=Ben-Shaul|first3=Yoram|last4=Yarom|first4=Yosef|last5=Wagner|first5=Shlomo|date=2015-12-16|title=Prolonged Intracellular Na+ Dynamics Govern Electrical Activity in Accessory Olfactory Bulb Mitral Cells|url=http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002319|journal=PLOS Biology|volume=13|issue=12|pages=e1002319|doi=10.1371/journal.pbio.1002319|issn=1545-7885|pmc=4684409|pmid=26674618}}</ref><ref>{{Cite journal|last=Scheuss|first=Volker|last2=Yasuda|first2=Ryohei|last3=Sobczyk|first3=Aleksander|last4=Svoboda|first4=Karel|date=2006-08-02|title=Nonlinear [Ca2+] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca2+ Extrusion|url=http://www.jneurosci.org/content/26/31/8183|journal=Journal of Neuroscience|language=en|volume=26|issue=31|pages=8183–8194|doi=10.1523/JNEUROSCI.1962-06.2006|issn=0270-6474|pmid=16885232}}</ref>

===Na<sup>+</sup>/Ca<sup>2+</sup> exchanger in the cardiac action potential===
The ability for the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger to reverse direction of flow manifests itself during the [[cardiac action potential]]. Due to the delicate role that Ca<sup>2+</sup> plays in the contraction of heart muscles, the cellular concentration of Ca<sup>2+</sup> is carefully controlled. During the resting potential, the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger takes advantage of the large extracellular Na+ concentration gradient to help pump Ca<sup>2+</sup> out of the cell.<ref name="nature">{{cite journal | vauthors = Bers DM | title = Cardiac excitation-contraction coupling | journal = Nature | volume = 415 | issue = 6868 | pages = 198–205 | date = Jan 2002 | pmid = 11805843 | doi = 10.1038/415198a | bibcode = 2002Natur.415..198B }}</ref> In fact, the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger is in the Ca<sup>2+</sup> efflux position most of the time. However, during the upstroke of the [[cardiac action potential]] there is a large influx of Na<sup>+</sup> ions. This depolarizes the cell and shifts the membrane potential in the positive direction. What results is a large increase in intracellular [Na<sup>+</sup>]. This causes the reversal of the Na<sup>+</sup>/Ca<sup>2+</sup> exchanger to pump Na<sup>+</sup> ions out of the cell and Ca<sup>2+</sup> ions into the cell.<ref name="nature"/> However, this reversal of the exchanger lasts only momentarily due to the internal rise in [Ca<sup>2+</sup>] as a result of the influx of Ca<sup>2+</sup> through the [[L-type calcium channel]], and the exchanger returns to its forward direction of flow, pumping Ca<sup>2+</sup> out of the cell.<ref name="nature"/>

While the exchanger normally works in the Ca<sup>2+</sup> efflux position (with the exception of early in the action potential), certain conditions can abnormally switch the exchanger to the reverse (Ca<sup>2+</sup> influx, Na<sup>+</sup> efflux) position. Listed below are several cellular and pharmaceutical conditions in which this happens.<ref name="nature"/>
*The internal [Na<sup>+</sup>] is higher than usual (like it is when digitalis glycoside medications block the Na<sup>+</sup>/K<sup>+</sup> -ATPase pump.)
*The [[sarcoplasmic reticulum]] release of Ca<sup>2+</sup> is inhibited.
*Other Ca<sup>2+</sup> influx channels are inhibited.
*If the action potential duration is prolonged.

==Structure==
Based on [[Protein structure prediction#Secondary structure|secondary structure]] and [[Hydrophobicity scales#Wimley-White whole residue hydrophobicity scales|hydrophobicity predictions]], NCX was initially predicted to have 9 [[Transmembrane domain|transmembrane helices]].<ref>{{cite journal | vauthors = Nicoll DA, Ottolia M, Philipson KD | title = Toward a topological model of the NCX1 exchanger | journal = Annals of the New York Academy of Sciences | volume = 976 | pages = 11–8 | date = Nov 2002 | pmid = 12502529 | doi=10.1111/j.1749-6632.2002.tb04709.x| bibcode = 2002NYASA.976...11N }}</ref> 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.<ref>{{cite journal | vauthors = Cai X, Lytton J | title = The cation/Ca(2+) exchanger superfamily: phylogenetic analysis and structural implications | journal = Molecular Biology and Evolution | volume = 21 | issue = 9 | pages = 1692–703 | date = Sep 2004 | pmid = 15163769 | doi = 10.1093/molbev/msh177 }}</ref> Inserted between the pseudo-symmetric halves is a cytoplasmic loop containing regulatory domains.<ref>{{cite journal | vauthors = Matsuoka S, Nicoll DA, Reilly RF, Hilgemann DW, Philipson KD | title = Initial localization of regulatory regions of the cardiac sarcolemmal Na(+)-Ca2+ exchanger | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 9 | pages = 3870–4 | date = May 1993 | pmid = 8483905 | doi=10.1073/pnas.90.9.3870 | pmc=46407| bibcode = 1993PNAS...90.3870M }}</ref> These regulatory domains have [[C2 domain]] like structures and are responsible for calcium regulation.<ref>{{cite journal | vauthors = Besserer GM, Ottolia M, Nicoll DA, Chaptal V, Cascio D, Philipson KD, Abramson J | title = The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 47 | pages = 18467–72 | date = Nov 2007 | pmid = 17962412 | doi = 10.1073/pnas.0707417104 | pmc=2141800| bibcode = 2007PNAS..10418467B }}</ref><ref>{{cite journal | vauthors = Nicoll DA, Sawaya MR, Kwon S, Cascio D, Philipson KD, Abramson J | title = The crystal structure of the primary Ca2+ sensor of the Na+/Ca2+ exchanger reveals a novel Ca2+ binding motif | journal = The Journal of Biological Chemistry | volume = 281 | issue = 31 | pages = 21577–81 | date = Aug 2006 | pmid = 16774926 | doi = 10.1074/jbc.C600117200 }}</ref> Recently, the structure of an [[archaea]]l NCX ortholog has been solved by [[X-ray crystallography]].<ref>{{cite journal | vauthors = Liao J, Li H, Zeng W, Sauer DB, Belmares R, Jiang Y | title = Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger | journal = Science | volume = 335 | issue = 6069 | pages = 686–90 | date = Feb 2012 | pmid = 22323814 | doi = 10.1126/science.1215759 | bibcode = 2012Sci...335..686L }}</ref> This clearly illustrates a [[protein dimer|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 [[Saccharomyces cerevisiae|yeast]] and [[bacteria]]. While structurally and functionally homologus, these structures illustrate novel [[Protein quaternary structure|oligomeric]] structures, substrate coupling, and regulation.<ref>{{cite journal | vauthors = Waight AB, Pedersen BP, Schlessinger A, Bonomi M, Chau BH, Roe-Zurz Z, Risenmay AJ, Sali A, Stroud RM | title = Structural basis for alternating access of a eukaryotic calcium/proton exchanger | journal = Nature | volume = 499 | issue = 7456 | pages = 107–10 | date = Jul 2013 | pmid = 23685453 | pmc = 3702627 | doi = 10.1038/nature12233 | bibcode = 2013Natur.499..107W }}</ref><ref>{{cite journal | vauthors = Nishizawa T, Kita S, Maturana AD, Furuya N, Hirata K, Kasuya G, Ogasawara S, Dohmae N, Iwamoto T, Ishitani R, Nureki O | title = Structural basis for the counter-transport mechanism of a H+/Ca2+ exchanger | journal = Science | volume = 341 | issue = 6142 | pages = 168–72 | date = Jul 2013 | pmid = 23704374 | doi = 10.1126/science.1239002 | bibcode = 2013Sci...341..168N }}</ref><ref>{{cite journal | vauthors = Wu M, Tong S, Waltersperger S, Diederichs K, Wang M, Zheng L | title = Crystal structure of Ca2+/H+ antiporter protein YfkE reveals the mechanisms of Ca2+ efflux and its pH regulation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 28 | pages = 11367–72 | date = Jul 2013 | pmid = 23798403 | doi = 10.1073/pnas.1302515110 | bibcode = 2013PNAS..11011367W | pmc=3710832}}</ref>

==History==
In 1968, H Reuter and N Seitz published findings that, when Na<sup>+</sup> is removed from the medium surrounding a cell, the efflux of Ca<sup>2+</sup> is inhibited, and they proposed that there might be a mechanism for exchanging the two ions.<ref name="Dipolo"/><ref>{{cite journal | vauthors = Reuter H, Seitz N | title = The dependence of calcium efflux from cardiac muscle on temperature and external ion composition | journal = The Journal of Physiology | volume = 195 | issue = 2 | pages = 451–70 | date = Mar 1968 | pmid = 5647333 | pmc = 1351672 | doi =  10.1113/jphysiol.1968.sp008467| url = http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=5647333 }}</ref> In 1969, a group led by PF Baker that was experimenting using [[squid axon]]s published a finding that proposed that there exists a means of Na<sup>+</sup> exit from cells other than the [[sodium-potassium pump]].<ref name="Dipolo"/><ref>{{cite journal | vauthors = Baker PF, Blaustein MP, Hodgkin AL, Steinhardt RA | title = The influence of calcium on sodium efflux in squid axons | journal = The Journal of Physiology | volume = 200 | issue = 2 | pages = 431–58 | date = Feb 1969 | pmid = 5764407 | pmc = 1350476 | url = http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=5764407 | doi=10.1113/jphysiol.1969.sp008702}}</ref>

== See also ==
* [[Active transport]]
* [[Cardiac action potential]]
* [[Potassium-dependent sodium-calcium exchanger]]

== References ==
{{reflist|2}}

== External links ==
* {{MeshName|Sodium-calcium+exchanger}}
* [http://www.cvphysiology.com/Cardiac%20Function/CF023.htm Diagram at cvphysiology.com]
* Klabunde, RE. 2007. [http://www.cvphysiology.com/Cardiac%20Function/CF023.htm Cardiovascular Physiology Concepts: Calcium Exchange.]

{{Membrane transport proteins}}

[[Category:Solute carrier family]]