Sodium-calcium exchanger

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solute carrier family 8 (sodium/calcium exchanger), member 1
Identifiers
SymbolSLC8A1
Alt. symbolsNCX1
NCBI gene 6546
HGNC 11068
OMIM 182305
RefSeq NM_021097
UniProt P32418
Other data
Locus Chr. 2 p23-p21
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Structures Swiss-model
Domains InterPro
solute carrier family 8 (sodium-calcium exchanger), member 2
Identifiers
SymbolSLC8A2
NCBI gene 6543
HGNC 11069
OMIM 601901
RefSeq NM_015063
UniProt Q9UPR5
Other data
Locus Chr. 19 q13.2
Search for
Structures Swiss-model
Domains InterPro
solute carrier family 8 (sodium-calcium exchanger), member 3
Identifiers
SymbolSLC8A3
NCBI gene 6547
HGNC 11070
OMIM 607991
RefSeq NM_033262
UniProt P57103
Other data
Locus Chr. 14 q24.1
Search for
Structures Swiss-model
Domains InterPro

The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) 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+). A single calcium ion is exported 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]

Contents

The exchanger is usually found in the plasma membranes and the mitochondria and endoplasmic reticulum of excitable cells. [3] [4]

Function

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. [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] 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. [6] The Na+/Ca2+ exchanger complements the high affinity, low capacitance Ca2+-ATPase and together, they are involved in a variety of cellular functions including:

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.

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. [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] This effect may prolong calcium transients following bursts of neuronal activity, thus influencing neuronal information processing. [10] [11]

Na+/Ca2+ exchanger in the cardiac action potential

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. [12] 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. [12] 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. [12]

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. [12]

Structure

Based on secondary structure and hydrophobicity predictions, NCX was initially predicted to have 9 transmembrane helices. [13] 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. [14] Inserted between the pseudo-symmetric halves is a cytoplasmic loop containing regulatory domains. [15] These regulatory domains have C2 domain like structures and are responsible for calcium regulation. [16] [17] Recently, the structure of an archaeal NCX ortholog has been solved by X-ray crystallography. [18] 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. [19] [20] [21]

History

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] [22] 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] [23] 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.

See also

Related Research Articles

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Sodium–potassium pump</span> Enzyme found in the membrane of all animal cells

The sodium–potassium pump is an enzyme found in the membrane of all animal cells. It performs several functions in cell physiology.

<span class="mw-page-title-main">Depolarization</span> Change in a cells electric charge distribution

In biology, depolarization or hypopolarization is a change within a cell, during which the cell undergoes a shift in electric charge distribution, resulting in less negative charge inside the cell compared to the outside. Depolarization is essential to the function of many cells, communication between cells, and the overall physiology of an organism.

<span class="mw-page-title-main">Membrane potential</span> Electric potential difference between interior and exterior of a biological cell

Membrane potential is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is the energy per charge which is required to move a positive charge at constant velocity across the cell membrane from the exterior to the interior.

<span class="mw-page-title-main">Excitatory synapse</span> Sort of synapse

An excitatory synapse is a synapse in which an action potential in a presynaptic neuron increases the probability of an action potential occurring in a postsynaptic cell. Neurons form networks through which nerve impulses travels, each neuron often making numerous connections with other cells of neurons. These electrical signals may be excitatory or inhibitory, and, if the total of excitatory influences exceeds that of the inhibitory influences, the neuron will generate a new action potential at its axon hillock, thus transmitting the information to yet another cell.

<span class="mw-page-title-main">Resting potential</span> Static membrane potential in biology

The relatively static membrane potential of quiescent cells is called the resting membrane potential, as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential. The resting membrane potential has a value of approximately -70mV or -0.07V.

<span class="mw-page-title-main">Cardiac action potential</span> Biological process in the heart

Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generation capability. In healthy hearts, these cells form the cardiac pacemaker and are found in the sinoatrial node in the right atrium. They produce roughly 60–100 action potentials every minute. The action potential passes along the cell membrane causing the cell to contract, therefore the activity of the sinoatrial node results in a resting heart rate of roughly 60–100 beats per minute. All cardiac muscle cells are electrically linked to one another, by intercalated discs which allow the action potential to pass from one cell to the next. This means that all atrial cells can contract together, and then all ventricular cells.

<span class="mw-page-title-main">Antiporter</span> Class of transmembrane transporter protein

An antiporter is an integral membrane protein that uses secondary active transport to move two or more molecules in opposite directions across a phospholipid membrane. It is a type of cotransporter, which means that uses the energetically favorable movement of one molecule down its electrochemical gradient to power the energetically unfavorable movement of another molecule up its electrochemical gradient. This is in contrast to symporters, which are another type of cotransporter that moves two or more ions in the same direction, and primary active transport, which is directly powered by ATP.

<span class="mw-page-title-main">Repolarization</span> Change in membrane potential

In neuroscience, repolarization refers to the change in membrane potential that returns it to a negative value just after the depolarization phase of an action potential which has changed the membrane potential to a positive value. The repolarization phase usually returns the membrane potential back to the resting membrane potential. The efflux of potassium (K+) ions results in the falling phase of an action potential. The ions pass through the selectivity filter of the K+ channel pore.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in a cell's electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels.

<span class="mw-page-title-main">Cerberin</span> Chemical compound

Cerberin is a type of cardiac glycoside, found in the seeds of the dicotyledonous angiosperm genus Cerbera; including the suicide tree and the sea mango. As a cardiac glycoside, cerberin disrupts the function of the heart by blocking its sodium and potassium ATPase. Cerberin can be used as a treatment for heart failure and arrhythmia.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

Molecular neuroscience is a branch of neuroscience that observes concepts in molecular biology applied to the nervous systems of animals. The scope of this subject covers topics such as molecular neuroanatomy, mechanisms of molecular signaling in the nervous system, the effects of genetics and epigenetics on neuronal development, and the molecular basis for neuroplasticity and neurodegenerative diseases. As with molecular biology, molecular neuroscience is a relatively new field that is considerably dynamic.

Visual phototransduction is the sensory transduction process of the visual system by which light is detected by photoreceptor cells in the vertebrate retina. A photon is absorbed by a retinal chromophore, which initiates a signal cascade through several intermediate cells, then through the retinal ganglion cells (RGCs) comprising the optic nerve.

<span class="mw-page-title-main">Electrochemical gradient</span> Gradient of electrochemical potential, usually for an ion that can move across a membrane

An electrochemical gradient is a gradient of electrochemical potential, usually for an ion that can move across a membrane. The gradient consists of two parts:

<span class="mw-page-title-main">Calcium ATPase</span> Class of enzymes

Ca2+ ATPase is a form of P-ATPase that transfers calcium after a muscle has contracted. The two kinds of calcium ATPase are:

Plasma membrane Ca<sup>2+</sup> ATPase Transport protein

The plasma membrane Ca2+ ATPase (PMCA) is a transport protein in the plasma membrane of cells that functions as a calcium pump to remove calcium (Ca2+) from the cell. PMCA function is vital for regulating the amount of Ca2+ within all eukaryotic cells. There is a very large transmembrane electrochemical gradient of Ca2+ driving the entry of the ion into cells, yet it is very important that they maintain low concentrations of Ca2+ for proper cell signalling. Thus, it is necessary for cells to employ ion pumps to remove the Ca2+. The PMCA and the sodium calcium exchanger (NCX) are together the main regulators of intracellular Ca2+ concentrations. Since it transports Ca2+ into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the extracellular space.

Calcium pumps are a family of ion transporters found in the cell membrane of all animal cells. They are responsible for the active transport of calcium out of the cell for the maintenance of the steep Ca2+ electrochemical gradient across the cell membrane. Calcium pumps play a crucial role in proper cell signalling by keeping the intracellular calcium concentration roughly 10,000 times lower than the extracellular concentration. Failure to do so is one cause of muscle cramps.

Anoxic depolarization is a progressive and uncontrollable depolarization of neurons during stroke or brain ischemia in which there is an inadequate supply of blood to the brain. Anoxic depolarization is induced by the loss of neuronal selective membrane permeability and the ion gradients across the membrane that are needed to support neuronal activity. Normally, the Na+/K+-ATPase pump maintains the transmembrane gradients of K+ and Na+ ions, but with anoxic brain injury, the supply of energy to drive this pump is lost. The hallmarks of anoxic depolarization are increased concentrations of extracellular K+ ions, intracellular Na+ and Ca2+ ions, and extracellular glutamate and aspartate. Glutamate and aspartate are normally present as the brain's primary excitatory neurotransmitters, but high concentrations activate a number of downstream apoptotic and necrotic pathways. This results in neuronal dysfunction and brain death.

The Ca2+:cation antiporter (CaCA) family (TC# 2.A.19) is a member of the cation diffusion facilitator (CDF) superfamily. This family should not be confused with the Ca2+:H+ Antiporter-2 (CaCA2) Family (TC# 2.A.106) which belongs to the Lysine Exporter (LysE) Superfamily. Proteins of the CaCA family are found ubiquitously, having been identified in animals, plants, yeast, archaea and divergent bacteria. Members of this family facilitate the antiport of calcium ion with another cation.

References

  1. 1 2 3 4 5 6 Yu SP, Choi DW (Jun 1997). "Na(+)-Ca2+ exchange currents in cortical neurons: concomitant forward and reverse operation and effect of glutamate". The European Journal of Neuroscience. 9 (6): 1273–81. doi:10.1111/j.1460-9568.1997.tb01482.x. PMID   9215711. S2CID   23146698.
  2. 1 2 3 4 DiPolo R, Beaugé L (Jan 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. 1 2 Kiedrowski L, Brooker G, Costa E, Wroblewski JT (Feb 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. S2CID   38199890.
  4. ↑ Patterson M, Sneyd J, Friel DD (Jan 2007). "Depolarization-induced calcium responses in sympathetic neurons: relative contributions from Ca2+ entry, extrusion, ER/mitochondrial Ca2+ uptake and release, and Ca2+ buffering". The Journal of General Physiology. 129 (1): 29–56. doi:10.1085/jgp.200609660. PMC   2151609 . PMID   17190902.
  5. ↑ Carafoli E, Santella L, Branca D, Brini M (Apr 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. S2CID   43050133.
  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.{{cite book}}: |author5= has generic name (help)CS1 maint: multiple names: authors list (link)
  7. 1 2 Lilly, L: "Pathophysiology of Heart Disease", chapter 11: "Mechanisms of Cardiac Arrhythmias", Lippencott, Williams and Wilkens, 2007
  8. ↑ Bindokas VP, Miller RJ (Nov 1995). "Excitotoxic degeneration is initiated at non-random sites in cultured rat cerebellar neurons". The Journal of Neuroscience. 15 (11): 6999–7011. doi:10.1523/JNEUROSCI.15-11-06999.1995. PMC   6578035 . PMID   7472456. S2CID   25625938.
  9. ↑ Wolf JA, Stys PK, Lusardi T, Meaney D, Smith DH (Mar 2001). "Traumatic axonal injury induces calcium influx modulated by tetrodotoxin-sensitive sodium channels". The Journal of Neuroscience. 21 (6): 1923–30. doi:10.1523/JNEUROSCI.21-06-01923.2001. PMC   6762603 . PMID   11245677. S2CID   13912728.
  10. ↑ Zylbertal, Asaph; Kahan, Anat; Ben-Shaul, Yoram; Yarom, Yosef; Wagner, Shlomo (2015-12-16). "Prolonged Intracellular Na+ Dynamics Govern Electrical Activity in Accessory Olfactory Bulb Mitral Cells". PLOS Biology. 13 (12): e1002319. doi: 10.1371/journal.pbio.1002319 . ISSN   1545-7885. PMC   4684409 . PMID   26674618.
  11. ↑ Scheuss, Volker; Yasuda, Ryohei; Sobczyk, Aleksander; Svoboda, Karel (2006-08-02). "Nonlinear [Ca2+] Signaling in Dendrites and Spines Caused by Activity-Dependent Depression of Ca2+ Extrusion". Journal of Neuroscience. 26 (31): 8183–8194. doi: 10.1523/JNEUROSCI.1962-06.2006 . ISSN   0270-6474. PMC   6673787 . PMID   16885232.
  12. 1 2 3 4 Bers DM (Jan 2002). "Cardiac excitation-contraction coupling". Nature. 415 (6868): 198–205. Bibcode:2002Natur.415..198B. doi:10.1038/415198a. PMID   11805843. S2CID   4337201.
  13. ↑ Nicoll DA, Ottolia M, Philipson KD (Nov 2002). "Toward a topological model of the NCX1 exchanger". Annals of the New York Academy of Sciences. 976 (1): 11–8. Bibcode:2002NYASA.976...11N. doi:10.1111/j.1749-6632.2002.tb04709.x. PMID   12502529. S2CID   21425718.
  14. ↑ Cai X, Lytton J (Sep 2004). "The cation/Ca(2+) exchanger superfamily: phylogenetic analysis and structural implications". Molecular Biology and Evolution. 21 (9): 1692–703. doi: 10.1093/molbev/msh177 . PMID   15163769.
  15. ↑ Matsuoka S, Nicoll DA, Reilly RF, Hilgemann DW, Philipson KD (May 1993). "Initial localization of regulatory regions of the cardiac sarcolemmal Na(+)-Ca2+ exchanger". Proceedings of the National Academy of Sciences of the United States of America. 90 (9): 3870–4. Bibcode:1993PNAS...90.3870M. doi: 10.1073/pnas.90.9.3870 . PMC   46407 . PMID   8483905.
  16. ↑ Besserer GM, Ottolia M, Nicoll DA, Chaptal V, Cascio D, Philipson KD, Abramson J (Nov 2007). "The second Ca2+-binding domain of the Na+ Ca2+ exchanger is essential for regulation: crystal structures and mutational analysis". Proceedings of the National Academy of Sciences of the United States of America. 104 (47): 18467–72. Bibcode:2007PNAS..10418467B. doi: 10.1073/pnas.0707417104 . PMC   2141800 . PMID   17962412.
  17. ↑ Nicoll DA, Sawaya MR, Kwon S, Cascio D, Philipson KD, Abramson J (Aug 2006). "The crystal structure of the primary Ca2+ sensor of the Na+/Ca2+ exchanger reveals a novel Ca2+ binding motif". The Journal of Biological Chemistry. 281 (31): 21577–81. doi: 10.1074/jbc.C600117200 . PMID   16774926.
  18. ↑ Liao J, Li H, Zeng W, Sauer DB, Belmares R, Jiang Y (Feb 2012). "Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger". Science. 335 (6069): 686–90. Bibcode:2012Sci...335..686L. doi:10.1126/science.1215759. PMID   22323814. S2CID   206538351.
  19. ↑ Waight AB, Pedersen BP, Schlessinger A, Bonomi M, Chau BH, Roe-Zurz Z, Risenmay AJ, Sali A, Stroud RM (Jul 2013). "Structural basis for alternating access of a eukaryotic calcium/proton exchanger". Nature. 499 (7456): 107–10. Bibcode:2013Natur.499..107W. doi:10.1038/nature12233. PMC   3702627 . PMID   23685453.
  20. ↑ Nishizawa T, Kita S, Maturana AD, Furuya N, Hirata K, Kasuya G, Ogasawara S, Dohmae N, Iwamoto T, Ishitani R, Nureki O (Jul 2013). "Structural basis for the counter-transport mechanism of a H+/Ca2+ exchanger". Science. 341 (6142): 168–72. Bibcode:2013Sci...341..168N. doi:10.1126/science.1239002. PMID   23704374. S2CID   206549290.
  21. ↑ Wu M, Tong S, Waltersperger S, Diederichs K, Wang M, Zheng L (Jul 2013). "Crystal structure of Ca2+/H+ antiporter protein YfkE reveals the mechanisms of Ca2+ efflux and its pH regulation". Proceedings of the National Academy of Sciences of the United States of America. 110 (28): 11367–72. Bibcode:2013PNAS..11011367W. doi: 10.1073/pnas.1302515110 . PMC   3710832 . PMID   23798403.
  22. ↑ Reuter H, Seitz N (Mar 1968). "The dependence of calcium efflux from cardiac muscle on temperature and external ion composition". The Journal of Physiology. 195 (2): 451–70. doi:10.1113/jphysiol.1968.sp008467. PMC   1351672 . PMID   5647333.
  23. ↑ Baker PF, Blaustein MP, Hodgkin AL, Steinhardt RA (Feb 1969). "The influence of calcium on sodium efflux in squid axons". The Journal of Physiology. 200 (2): 431–58. doi:10.1113/jphysiol.1969.sp008702. PMC   1350476 . PMID   5764407.
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