sodium-calcium exchanger

The sodium–calcium exchanger is only one of the systems by which the cytoplasmic concentration of calcium ions in the cell is kept low. The 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.{{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 | s2cid = 43050133 }} 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. Such a primary transporter of calcium ions is present in the plasma membrane of most animal cells. 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.{{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://archive.org/details/basicneurochemis0005unse | isbn=0-7817-0104-X | url-access=registration }} The Na⁺/Ca²⁺ exchanger complements the high affinity, low capacitance Ca²⁺-ATPase and together, they are involved in a variety of cellular functions including:

• control of neurosecretion
• activity of photoreceptor cells
• cardiac muscle relaxation
• maintenance of Ca²⁺ concentration in the sarcoplasmic reticulum in cardiac cells
• maintenance of Ca²⁺ concentration in the endoplasmic reticulum of both excitable and nonexcitable cells
• excitation-contraction coupling
• maintenance of low Ca²⁺ concentration in the mitochondria

The exchanger is also implicated in the cardiac electrical conduction abnormality known as delayed afterdepolarization.Lilly, L: "Pathophysiology of Heart Disease", chapter 11: "Mechanisms of Cardiac Arrhythmias", Lippencott, Williams and Wilkens, 2007 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. 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. In addition, as with other transport proteins, the amount and direction of transport depends on transmembrane substrate gradients. 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. However, it also means that, when intracellular levels of Na⁺ rise beyond a critical point, the NCX begins importing Ca²⁺.{{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 | doi = 10.1523/JNEUROSCI.15-11-06999.1995 | pmid = 7472456 | pmc = 6578035 | s2cid = 25625938 | url = }}{{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 | doi = 10.1523/JNEUROSCI.21-06-01923.2001 | pmid = 11245677 | pmc = 6762603 | s2cid = 13912728 | url = }} 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. This effect may prolong calcium transients following bursts of neuronal activity, thus influencing neuronal information processing.{{Cite journal|last1=Zylbertal|first1=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|journal=PLOS Biology|volume=13|issue=12|pages=e1002319|doi=10.1371/journal.pbio.1002319|issn=1545-7885|pmc=4684409|pmid=26674618 |doi-access=free }}{{Cite journal|last1=Scheuss|first1=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|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|pmc=6673787|doi-access=free}}

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.{{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 | s2cid = 4337201 }} 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. 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.

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.

• The internal [Na⁺] is higher than usual (like it is when digoxin and other cardiac 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.{{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 | issue = 1 | pmid = 12502529 | doi=10.1111/j.1749-6632.2002.tb04709.x| bibcode = 2002NYASA.976...11N | s2cid = 21425718 }} 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.{{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 | doi-access = free }} Inserted between the pseudo-symmetric halves is a cytoplasmic loop containing regulatory domains.{{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 | doi-access = free }} These regulatory domains have C2 domain like structures and are responsible for calcium regulation.{{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 | doi-access = free }}{{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 | doi-access = free }} Recently, the structure of an archaeal NCX ortholog has been solved by X-ray crystallography.{{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 | s2cid = 206538351 }} 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 exchangers (CAX) have been solved from yeast and bacteria. While structurally and functionally homologus, these structures illustrate novel oligomeric structures, substrate coupling, and regulation.{{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 }}{{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 | s2cid = 206549290 }}{{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| doi-access = free }}

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.{{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 }} 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.{{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}}

Digitalis, more commonly known as foxglove, is known to have a large effect on the Na/K ATPase, ultimately causing a more forceful contraction of the heart. The plant contains compounds that inhibit the sodium potassium pump which lowers the sodium electrochemical gradient. This makes the pumping of calcium out of the cell less efficient, which leads to a more forceful contraction of the heart. For individuals with weak hearts, it is sometimes provided to pump the heart with heavier contractile force. However, it can also cause hypertension because it increases the contractile force of the heart.

• Sodium–potassium pump
• Active transport
• Cardiac action potential
• Potassium-dependent sodium-calcium exchanger

{{reflist|2}}

• {{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