solute carrier family 8 (sodium/calcium exchanger), member 1 Identifiers 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 Identifiers 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 Identifiers 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. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.
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. 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. 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. 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:
- 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
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+ 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.
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. In 1969, a group led by PF Baker that was experimenting using squid axons published a finding that propsed that there exists a means of Na+ exit from cells other than the sodium-potassium pump.
- ^ 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.
- ^ 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. http://physrev.physiology.org/cgi/content/abstract/86/1/155.
- ^ 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.
- ^ 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2151609.
- ^ 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.
- ^ 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 078170104X. http://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.
- ^ 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. http://www.jneurosci.org/cgi/reprint/15/11/6999.
- ^ 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. http://www.jneurosci.org/cgi/content/full/21/6/1923.
- ^ 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. http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=5647333.
- ^ 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. http://www.jphysiol.org/cgi/pmidlookup?view=long&pmid=5764407.
- MeSH Sodium-calcium+exchanger
- Diagram at cvphysiology.com
- Klabunde, RE. 2007. Cardiovascular Physiology Concepts: Calcium Exchange.
By group SLC1–10
- (6) sodium- and chloride- dependent sodium:neurotransmitter symporters (SLC6A1, SLC6A2, SLC6A3, SLC6A4, SLC6A5, SLC6A6, SLC6A7, SLC6A8, SLC6A9, SLC6A10, SLC6A11, SLC6A12, SLC6A13, SLC6A14, SLC6A15, SLC6A16, SLC6A17, SLC6A18, SLC6A19, SLC6A20)
- (7) cationic amino-acid transporter/glycoprotein-associated (SLC7A1, SLC7A2, SLC7A3, SLC7A4) glycoprotein-associated/light or catalytic subunits of heterodimeric amino-acid transporters (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A9, SLC7A10, SLC7A11, SLC7A13, SLC7A14)
- (8) Na+/Ca2+ exchanger (SLC8A1, SLC8A2, SLC8A3)
- (9) Na+/H+ exchanger (SLC9A1, SLC9A2, SLC9A3, SLC9A4, SLC9A5, SLC9A6, SLC9A7, SLC9A8, SLC9A9, SLC9A10, SLC9A11)
- (12) electroneutral cation-Cl cotransporter (SLC12A1, SLC12A1, SLC12A2, SLC12A3, SLC12A4, SLC12A5, SLC12A6, SLC12A7, SLC12A8, SLC12A9)
- (15) proton oligopeptide cotransporter (SLC15A1, SLC15A2, SLC15A3, SLC15A4)
- (16) monocarboxylate transporter (SLC16A1, SLC16A2, SLC16A3, SLC16A4, SLC16A5, SLC16A6, SLC16A7, SLC16A8, SLC16A9, SLC16A10, SLC16A11, SLC16A12, SLC16A13, SLC16A14)
- (17) vesicular glutamate transporter (SLC17A1, SLC17A2, SLC17A3, SLC17A4, SLC17A5, SLC17A6, SLC17A7, SLC17A8, SLC17A9)
- (21) organic anion transporting (SLCO1A2, SLCO1B1, SLCO1B3, SLCO1B4, SLCO1C1) (SLCO2A1, SLCO2B1) (SLCO3A1) (SLCO4A1, SLCO4C1) (SLCO5A1) (SLCO6A1)
- (22) organic cation/anion/zwitterion transporter (SLC22A1, SLC22A2, SLC22A3, SLC22A4, SLC22A5, SLC22A6, SLC22A7, SLC22A8, SLC22A9, SLC22A10, SLC22A11, SLC22A12, SLC22A13, SLC22A14, SLC22A15, SLC22A16, SLC22A17, SLC22A18, SLC22A19, SLC22A20)
- (24) Na+/(Ca2+-K+) exchanger (SLC24A1, SLC24A2, SLC24A3, SLC24A4, SLC24A5, SLC24A6)
- (25) mitochondrial carrier (SLC25A1, SLC25A2, SLC25A3, SLC25A4, SLC25A5, SLC25A6, SLC25A7, SLC25A8, SLC25A9, SLC25A10, SLC25A11, SLC25A12, SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A18, SLC25A19, SLC25A20, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25, SLC25A26, SLC25A27, SLC25A28, SLC25A29, SLC25A30, SLC25A31, SLC25A32, SLC25A33, SLC25A34, SLC25A35, SLC25A36, SLC25A37, SLC25A38, SLC25A39, SLC25A40, SLC25A41, SLC25A42, SLC25A43, SLC25A44, SLC25A45, SLC25A46)
- (26) multifunctional anion exchanger (SLC26A1, SLC26A2, SLC26A3, SLC26A4, SLC26A5, SLC26A6, SLC26A7, SLC26A8, SLC26A9, SLC26A10, SLC26A11)
- (32) vesicular inhibitory amino-acid transporter (SLC32A1)
- (33) Acetyl-CoA transporter (SLC33A1)
- (35) nucleoside-sugar transporter (SLC35A1, SLC35A2, SLC35A3, SLC35A4, SLC35A5) (SLC35B1, SLC35B2, SLC35B3, SLC35B4) (SLC35C1, SLC35C2) (SLC35D1, SLC35D2, SLC35D3) (SLC35E1, SLC35E2, SLC35E3, SLC35E4)
- (36) proton-coupled amino-acid transporter (SLC36A1, SLC36A2, SLC36A3, SLC36A4)36A2 ·
- (37) sugar-phosphate/phosphate exchanger (SLC37A1, SLC37A2, SLC37A3, SLC37A4)
- (38) System A & N, sodium-coupled neutral amino-acid transporter (SLC38A1, SLC38A2, SLC38A3, SLC38A4, SLC38A5, SLC38A6, SLC38A10)
- (39) metal ion transporter (SLC39A1, SLC39A2, SLC39A3, SLC39A4, SLC39A5, SLC39A6, SLC39A7, SLC39A8, SLC39A9, SLC39A10, SLC39A11, SLC39A12, SLC39A13, SLC39A14)
- (40) basolateral iron transporter (SLC40A1)
- (41) MgtE-like magnesium transporter (SLC41A1, SLC41A2, SLC41A3)
- (43) Na+-independent, system-L like amino-acid transporter (SLC43A1, SLC43A2, SLC43A3)
- (45) Putative sugar transporter (SLC45A1, SLC45A2, SLC54A3, SLC45A4)
- (46) Folate transporter (SLC46A1, SLC46A2)
- (48) Heme transporter
SLCO1–4 Ion pumps
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