Plasma membrane Ca2+ ATPase: Difference between revisions

Content deleted Content added

Inline

Latest revision as of 16:54, 13 August 2024

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.^[1]^[2] 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⁺.^[3] The PMCA and the sodium calcium exchanger (NCX) are together the main regulators of intracellular Ca²⁺ concentrations.^[2] Since it transports Ca²⁺ into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the extracellular space.^[4]

PMCAs belong to the family of P-type primary ion transport ATPases which form aspartyl phosphate intermediates.^[2]

Various forms of PMCA are expressed in different tissues, including the brain.^[5]

Actions

The pump is powered by the hydrolysis of adenosine triphosphate (ATP), with a stoichiometry of one Ca²⁺ ion removed for each molecule of ATP hydrolysed. It binds tightly to Ca²⁺ ions (has a high affinity, with a K_m of 100 to 200 nM) but does not remove Ca²⁺ at a very fast rate.^[6] This is in contrast to the NCX, which has a low affinity and a high capacity. Thus, the PMCA is effective at binding Ca²⁺ even when its concentrations within the cell are very low, so it is suited for maintaining Ca²⁺ at its normally very low levels.^[3] Calcium is an important second messenger, so its levels must be kept low in cells to prevent noise and keep signalling accurate.^[7] The NCX is better suited for removing large amounts of Ca²⁺ quickly, as is needed in neurons after an action potential. Thus the activities of the two types of pump complement each other.

The PMCA functions in a similar manner to other p-type ion pumps.^[3] ATP transfers a phosphate to the PMCA, which forms a phosphorylated intermediate.^[3]

Ca²⁺/calmodulin binds and further activates the PMCA, increasing the affinity of the protein's Ca²⁺-binding site 20 to 30 times.^[6] Calmodulin also increases the rate at which the pump extrudes Ca²⁺ from the cell, possibly up to tenfold.^[3]

In brain tissue, it has been postulated that certain types of PMCA are important for regulating synaptic activity, since the PMCA is involved in regulating the amount of calcium within the cell at the synapse,^[5] and Ca²⁺ is involved in release of synaptic vesicles. Additionally, it has been shown that PMCA activity is modulated and partly powered by glycolysis in neuronal somata and dendrites.^[8] Presumably, it is due to PMCA proximity to glucose transporters in the plasma membrane.

Structure

The structure of the PMCA is similar to that of the SERCA calcium pumps, which are responsible for removing calcium from the cytoplasm into the lumen of the sarcoplasmic reticulum.^[2] Calcium tends to have a slightly lower affinity for PMCA pumps than for SERCA pumps.^[9] It is thought that the PMCA pump has 10 segments that cross the plasma membrane, with both C and N termini on the inside of the cell.^[2] At the C terminus, there is a long "tail" of between 70 and 200 amino acids in length.^[2] This tail is thought to be responsible for regulation of the pump.^[2] PMCA pumps have a molecular mass of around 140 kDa.^[10]

Isoforms

There are four isoforms of PMCA, called PMCA 1 through 4.^[5]

ATP2B1 - PMCA1
ATP2B2 - PMCA2
ATP2B3 - PMCA3
ATP2B4 - PMCA4

Each isoform is coded by a different gene and is expressed in different areas of the body.^[5] Alternate splicing of the mRNA transcripts of these genes results in different subtypes of these isoforms.^[2] Over 20 splice variants have been identified so far.^[2]

Three PMCA isoforms, PMCA1, PMCA2, and PMCA3, occur in the brain in varying distributions.^[6] PMCA1 is ubiquitous throughout all tissues in humans, and without it embryos do not survive.^[4] Lack of PMCA4, which is also very common in many tissues, is survivable, but leads to infertility in males.^[4] PMCA types 2 and 3 are activated more quickly and are, therefore, better suited to excitable cell types such as those in nervous and muscle tissue, which experiences large influxes of Ca²⁺ when excited.^[5] PMCA types 1, 2, and 4 have been found in glial cells called astrocytes in mammals, though it was previously thought that only the NCX was present in glia.^[11] Astrocytes help to maintain ionic balance in the extracellular space in the brain.

Knock-out of PMCA2 causes inner ear problems, including hearing loss and problems with balance.^[12]

PMCA4 exists in caveolae.^[12] Isoform PMCA4b interacts with nitric oxide synthase and reduces synthesis of nitric oxide by that enzyme.^[12]

PMCA isoform 4 has a molecular weight of 134,683, calculated from its sequence.^[13] This is in good agreement with the results of SDS gel electrophoresis.^[14]

Pathology

When the PMCA fails to function properly, disease can result. Improperly functioning PMCA proteins have been found associated with conditions such as sensorineural deafness, diabetes, and hypertension.^[4]

In excitotoxicity, a process in which excessive amounts of the neurotransmitter glutamate overactivate neurons, resulting in excessive influx of Ca²⁺ into cells, the activity of the PMCA may be insufficient to remove the excess Ca²⁺.

In breast tissue, mammary epithelial cells express PMCA2, which transports calcium across the apical surface of the cells into milk. PMCA2 expression falls on weaning, leading to calcium-induced apoptosis and mammary gland involution. Persistent PMCA2 expression in certain breast cancers lowers calcium levels inside malignant cells, allowing them to avoid apoptosis. These tumors are also usually positive for the HER2 protein, tend to involve the lymph nodes, and are more common among young women, which could help explain their worse prognosis compared with postmenopausal women.^[15]

Curcumin can bind to the PMCA, inducing a conformational change that prevents ATP from binding.^[16]

History

PMCAs were first discovered in the 1960s in the membranes of red blood cells.^[2] The presence of an ATPase was discovered in the membranes in 1961, and then in 1966 it was discovered that these ATPases pump Ca²⁺ out of the cytosol.^[3]

PMCA was first purified from red blood cell membranes in 1979.^[17]^[18]

References

^ Jensen, Thomas P.; Buckby, Lucy E.; Empson, Ruth M. (2004). "Expression of plasma membrane Ca²⁺ ATPase family members and associated synaptic proteins in acute and cultured organotypic hippocampal slices from rat". Developmental Brain Research. 152 (2): 129–136. doi:10.1016/j.devbrainres.2004.06.004. PMID 15351500.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Strehler, Emanuel E.; Zacharias, David A. (2001). "Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps". Physiol. Rev. 81 (1): 21–50. doi:10.1152/physrev.2001.81.1.21. PMID 11152753. S2CID 9062253.
^ ^a ^b ^c ^d ^e ^f Carafoli, E. (1991). "Calcium pump of the plasma membrane". Physiol. Rev. 71 (1): 129–153. doi:10.1152/physrev.1991.71.1.129. PMID 1986387.
^ ^a ^b ^c ^d Talarico, Ernest F. Jr.; Kennedy, Brian G.; Marfurt, Carl F.; Loeffler, Karin U.; Mangini, Nancy J. (2005). "Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium". Mol. Vis. 11: 169–178. PMID 15765049. Retrieved 2013-12-25.
^ ^a ^b ^c ^d ^e Jensen, Thomas P.; Filoteo, Adelaida G.; Knopfel, Thomas; Empson, Ruth M. (2006). "Pre-synaptic plasma membrane isoform 2a regulates excitatory synaptic transmission in rat hippocampal CA3". J. Physiol. 579 (1): 85–99. doi:10.1113/jphysiol.2006.123901. PMC 2075377. PMID 17170045. Retrieved 2007-01-13.
^ ^a ^b ^c Albers, R. Wayne; Siegel, George J. (1999). "5. Membrane Transport". In Siegel, George J.; et al. (eds.). Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (6th ed.). Philadelphia: Lippincott-Raven. ATP-Dependent Ca2+ Pumps. ISBN 978-0-397-51820-3. OCLC 39013748. Retrieved 2013-12-25.
^ Burette, Alain; Weinberg, Richard J. (February 2007). "Perisynaptic organization of plasma membrane calcium pumps in cerebellar cortex". J. Comp. Neurol. 500 (6) (published 2006-12-20): 1127–1135. doi:10.1002/cne.21237. PMID 17183553. S2CID 22110231.
^ Ivannikov, Maxim V.; Sugimori, Mutsuyuki; Llinás, Rodolfo R. (2010). "Calcium clearance and its energy requirements in cerebellar neurons". Cell Calcium. 47 (6): 507–513. doi:10.1016/j.ceca.2010.04.004. PMC 2900537. PMID 20510449.
^ Lopez, Jose R.; Allen, Paul D. (2012-01-01), Hill, Joseph A.; Olson, Eric N. (eds.), "Chapter 56 - Control of Resting Ca2+ Concentration in Skeletal Muscle", Muscle, Boston/Waltham: Academic Press, pp. 801–810, doi:10.1016/b978-0-12-381510-1.00056-9, ISBN 978-0-12-381510-1, retrieved 2020-11-08
^ Edes, Istvan; Kranias, Evangelia G. (1995-01-01), Sperelakis, NICHOLAS (ed.), "13 - Ca2+-ATPases", Cell Physiology Source Book, Academic Press, pp. 156–165, doi:10.1016/b978-0-12-656970-4.50019-1, ISBN 978-0-12-656970-4, retrieved 2020-11-08
^ Fresu, Luigia; Dehpour, Ahmed; Genazzani, Armando A.; Carafoli, Ernesto; Guerini, Danilo (November 1999). "Plasma membrane calcium ATPase isoforms in astrocytes". Glia. 28 (2) (published 1999-10-22): 150–155. doi:10.1002/(SICI)1098-1136(199911)28:2<150::AID-GLIA6>3.0.CO;2-7. PMID 10533058. S2CID 44343760.
^ ^a ^b ^c Schuh, Kai; Uldrijan, Stjepan; Telkamp, Myriam; Röthlein, Nicola; Neyses, Ludwig (2001). "The plasmamembrane calmodulin–dependent calcium pump : a major regulator of nitric oxide synthase I". J. Cell Biol. 155 (2): 201–205. doi:10.1083/jcb.200104131. PMC 2198825. PMID 11591728.
^ Verma, Anil K.; Filoteo, Adelaida G.; Stanford, David R.; Wieben, Eric D.; Penniston, John T. (1988). "Complete Primary Structure of a Human Plasma Membrane Ca²⁺ Pump". J. Biol. Chem. 263 (28): 14152–14159. doi:10.1016/S0021-9258(18)68198-0. PMID 2844759. Retrieved 2013-12-25.
^ Graf, Ernst; Verma, Anil K.; Gorski, Jeffrey P.; Lopaschuk, Gary; Niggli, Verena; Zurini, Mauro; Carafoli, E.; Penniston, John T. (1982). "Molecular Properties of Calcium-Pumping ATPase from Human Erythrocytes". Biochemistry. 21 (18): 4511–4516. doi:10.1021/bi00261a049. PMID 6215062.
^ VanHouten, Joshua; Sullivan, Catherine; Bazinet, Caroline; Ryoo, Tom; Camp, Robert; Rimm, David L.; Chung, Gina; Wysolmerski, John (2010-06-22). "PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer". Proc. Natl. Acad. Sci. U.S.A. 107 (25) (published 2010-06-04): 11405–11410. Bibcode:2010PNAS..10711405V. doi:10.1073/pnas.0911186107. PMC 2895115. PMID 20534448.
^ Shehzad, Adeeb; Shahzad, Raheem; Lee, Young Sup (2014-01-01), Bathaie, S. Zahra; Tamanoi, Fuyuhiko (eds.), "Chapter Eight - Curcumin: A Potent Modulator of Multiple Enzymes in Multiple Cancers", The Enzymes, Natural Products and Cancer Signaling: Isoprenoids, Polyphenols and Flavonoids, 36, Academic Press: 149–174, doi:10.1016/b978-0-12-802215-3.00008-2, PMID 27102703, retrieved 2020-11-08
^ Niggli, Verena; Penniston, John T.; Carafoli, Ernesto (1979). "Purification of the (Ca²⁺-Mg²⁺) ATPase from Human Erythrocyte Membranes using a Calmodulin Affinity Column". J. Biol. Chem. 254 (20): 9955–9958. doi:10.1016/S0021-9258(19)86652-8. PMID 158595. Retrieved 2013-12-25..
^ Penniston, John T.; Gfiloteo, Adelaida; McDonough, Carol S.; Carafoli, Ernesto (1988). "Purification, reconstitution, and regulation of plasma membrane Ca₂⁺-pumps". Biomembranes Part Q: ATP-Driven Pumps and Related Transport: Calcium, Proton, and Potassium Pumps. Methods in Enzymology. Vol. 157. pp. 340–351. doi:10.1016/0076-6879(88)57089-1. ISBN 978-0-12-182058-9. PMID 2976465..

External links

Plasma+Membrane+Calcium-Transporting+ATPases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

[1] Jensen, Thomas P.; Buckby, Lucy E.; Empson, Ruth M. (2004). "Expression of plasma membrane Ca²⁺ ATPase family members and associated synaptic proteins in acute and cultured organotypic hippocampal slices from rat". Developmental Brain Research. 152 (2): 129–136. doi:10.1016/j.devbrainres.2004.06.004. PMID 15351500.

[Strehler-2] ^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Strehler, Emanuel E.; Zacharias, David A. (2001). "Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps". Physiol. Rev. 81 (1): 21–50. doi:10.1152/physrev.2001.81.1.21. PMID 11152753. S2CID 9062253.

[Carafoli-3] ^ ^a ^b ^c ^d ^e ^f Carafoli, E. (1991). "Calcium pump of the plasma membrane". Physiol. Rev. 71 (1): 129–153. doi:10.1152/physrev.1991.71.1.129. PMID 1986387.

[Talarico-4] Talarico, Ernest F. Jr.; Kennedy, Brian G.; Marfurt, Carl F.; Loeffler, Karin U.; Mangini, Nancy J. (2005). "Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium". Mol. Vis. 11: 169–178. PMID 15765049. Retrieved 2013-12-25.

[Jensen06-5] Jensen, Thomas P.; Filoteo, Adelaida G.; Knopfel, Thomas; Empson, Ruth M. (2006). "Pre-synaptic plasma membrane isoform 2a regulates excitatory synaptic transmission in rat hippocampal CA3". J. Physiol. 579 (1): 85–99. doi:10.1113/jphysiol.2006.123901. PMC 2075377. PMID 17170045. Retrieved 2007-01-13.

[Siegel-6] Albers, R. Wayne; Siegel, George J. (1999). "5. Membrane Transport". In Siegel, George J.; et al. (eds.). Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (6th ed.). Philadelphia: Lippincott-Raven. ATP-Dependent Ca2+ Pumps. ISBN 978-0-397-51820-3. OCLC 39013748. Retrieved 2013-12-25.

[7] Burette, Alain; Weinberg, Richard J. (February 2007). "Perisynaptic organization of plasma membrane calcium pumps in cerebellar cortex". J. Comp. Neurol. 500 (6) (published 2006-12-20): 1127–1135. doi:10.1002/cne.21237. PMID 17183553. S2CID 22110231.

[8] Ivannikov, Maxim V.; Sugimori, Mutsuyuki; Llinás, Rodolfo R. (2010). "Calcium clearance and its energy requirements in cerebellar neurons". Cell Calcium. 47 (6): 507–513. doi:10.1016/j.ceca.2010.04.004. PMC 2900537. PMID 20510449.

[9] Lopez, Jose R.; Allen, Paul D. (2012-01-01), Hill, Joseph A.; Olson, Eric N. (eds.), "Chapter 56 - Control of Resting Ca2+ Concentration in Skeletal Muscle", Muscle, Boston/Waltham: Academic Press, pp. 801–810, doi:10.1016/b978-0-12-381510-1.00056-9, ISBN 978-0-12-381510-1, retrieved 2020-11-08

[10] Edes, Istvan; Kranias, Evangelia G. (1995-01-01), Sperelakis, NICHOLAS (ed.), "13 - Ca2+-ATPases", Cell Physiology Source Book, Academic Press, pp. 156–165, doi:10.1016/b978-0-12-656970-4.50019-1, ISBN 978-0-12-656970-4, retrieved 2020-11-08

[Fresu-11] Fresu, Luigia; Dehpour, Ahmed; Genazzani, Armando A.; Carafoli, Ernesto; Guerini, Danilo (November 1999). "Plasma membrane calcium ATPase isoforms in astrocytes". Glia. 28 (2) (published 1999-10-22): 150–155. doi:10.1002/(SICI)1098-1136(199911)28:2<150::AID-GLIA6>3.0.CO;2-7. PMID 10533058. S2CID 44343760.

[Schuh-12] Schuh, Kai; Uldrijan, Stjepan; Telkamp, Myriam; Röthlein, Nicola; Neyses, Ludwig (2001). "The plasmamembrane calmodulin–dependent calcium pump : a major regulator of nitric oxide synthase I". J. Cell Biol. 155 (2): 201–205. doi:10.1083/jcb.200104131. PMC 2198825. PMID 11591728.

[13] Verma, Anil K.; Filoteo, Adelaida G.; Stanford, David R.; Wieben, Eric D.; Penniston, John T. (1988). "Complete Primary Structure of a Human Plasma Membrane Ca²⁺ Pump". J. Biol. Chem. 263 (28): 14152–14159. doi:10.1016/S0021-9258(18)68198-0. PMID 2844759. Retrieved 2013-12-25.

[14] Graf, Ernst; Verma, Anil K.; Gorski, Jeffrey P.; Lopaschuk, Gary; Niggli, Verena; Zurini, Mauro; Carafoli, E.; Penniston, John T. (1982). "Molecular Properties of Calcium-Pumping ATPase from Human Erythrocytes". Biochemistry. 21 (18): 4511–4516. doi:10.1021/bi00261a049. PMID 6215062.

[15] VanHouten, Joshua; Sullivan, Catherine; Bazinet, Caroline; Ryoo, Tom; Camp, Robert; Rimm, David L.; Chung, Gina; Wysolmerski, John (2010-06-22). "PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer". Proc. Natl. Acad. Sci. U.S.A. 107 (25) (published 2010-06-04): 11405–11410. Bibcode:2010PNAS..10711405V. doi:10.1073/pnas.0911186107. PMC 2895115. PMID 20534448.

[16] Shehzad, Adeeb; Shahzad, Raheem; Lee, Young Sup (2014-01-01), Bathaie, S. Zahra; Tamanoi, Fuyuhiko (eds.), "Chapter Eight - Curcumin: A Potent Modulator of Multiple Enzymes in Multiple Cancers", The Enzymes, Natural Products and Cancer Signaling: Isoprenoids, Polyphenols and Flavonoids, 36, Academic Press: 149–174, doi:10.1016/b978-0-12-802215-3.00008-2, PMID 27102703, retrieved 2020-11-08

[17] Niggli, Verena; Penniston, John T.; Carafoli, Ernesto (1979). "Purification of the (Ca²⁺-Mg²⁺) ATPase from Human Erythrocyte Membranes using a Calmodulin Affinity Column". J. Biol. Chem. 254 (20): 9955–9958. doi:10.1016/S0021-9258(19)86652-8. PMID 158595. Retrieved 2013-12-25..

[18] Penniston, John T.; Gfiloteo, Adelaida; McDonough, Carol S.; Carafoli, Ernesto (1988). "Purification, reconstitution, and regulation of plasma membrane Ca₂⁺-pumps". Biomembranes Part Q: ATP-Driven Pumps and Related Transport: Calcium, Proton, and Potassium Pumps. Methods in Enzymology. Vol. 157. pp. 340–351. doi:10.1016/0076-6879(88)57089-1. ISBN 978-0-12-182058-9. PMID 2976465..

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

@@ Line 1: / Line 1: @@
-{{About|the ion transporter |the protein assay|Protein Misfolding Cyclic Amplification}}
+{{Short description|Transport protein}}{{redirect|PMCA|the protein assay|Protein misfolding cyclic amplification}}
 {{DISPLAYTITLE:Plasma membrane Ca<sup>2+</sup> ATPase}}
 [[Image:Calcium atpase.png|thumb|250px|Rendered image of the Ca<sup>2+</sup> pump]]
-The '''plasma membrane Ca<sup>2+</sup> ATPase''' ('''PMCA''') is a [[transport protein]] in the [[plasma membrane]] of [[cell (biology)|cell]]s and functions to remove [[calcium]] (Ca<sup>2+</sup>) from the cell.  PMCA function is vital for regulating the amount of Ca<sup>2+</sup> within all [[eukaryotic]] cells.<ref>{{cite journal | last =Jensen  | first =Thomas P. | title = Expression of plasma membrane Ca<sup>2+</sup> ATPase family members and associated synaptic proteins in acute and cultured organotypic hippocampal slices from rat. | journal =[[Dev. Brain Res.]] | volume =152 | issue = 2| pages =129–136 | year =2004 | url =http://www.sciencedirect.com/science/article/pii/S0165380604001993 | doi = 10.1016/j.devbrainres.2004.06.004| pmid = 15351500 | accessdate =2013-12-25|first2 = Lucy E.|last2 = Buckby|first3 = Ruth M.|last3 = Empson}}{{Closed access}}</ref><ref name="Strehler">{{cite journal | last =Strehler  | first =Emanuel E. | title =Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps| journal =[[Physiol. Rev.]] | volume = 81| issue = 1| pages =21–50 | year =2001 | url = http://physrev.physiology.org/content/81/1/21.full | pmid =11152753 | accessdate =2013-12-25 |first2 = David A.|last2 = Zacharias}}{{Open access}}</ref>  There is a very large transmembrane [[electrochemical gradient]] of Ca<sup>2+</sup> driving the entry of the [[ion]] into cells, yet it is very important that they maintain low [[concentration]]s of Ca<sup>2+</sup> for proper [[cell signalling]]. Thus, it is necessary for cells to employ [[Ion transporter|ion pump]]s to remove the Ca<sup>2+</sup>.<ref name="Carafoli">{{cite journal | last =Carafoli | first =E | authorlink = | coauthors = | title =Calcium pump of the plasma membrane | journal =Physiological Reviews | volume =71 | issue =1 | pages =129–153 | publisher = | year =1991 | url =http://physrev.physiology.org/cgi/reprint/71/1/129?ijkey=07dce5327b657cc65fb6152751c728391912b332&keytype2=tf_ipsecsha| doi = | pmid =1986387 | accessdate =2007-01-30 }}</ref>
+The '''plasma membrane Ca<sup>2+</sup> ATPase''' ('''PMCA''') is a [[transport protein]] in the [[plasma membrane]] of [[cell (biology)|cell]]s that functions as a calcium pump to remove [[calcium]] (Ca<sup>2+</sup>) from the cell.  PMCA function is vital for regulating the amount of Ca<sup>2+</sup> within all [[eukaryotic]] cells.<ref>{{cite journal | last1 =Jensen  | first1 =Thomas P. | title = Expression of plasma membrane Ca<sup>2+</sup> ATPase family members and associated synaptic proteins in acute and cultured organotypic hippocampal slices from rat. | journal =[[Developmental Brain Research]] | volume =152 | issue = 2| pages =129–136 | year =2004 | doi = 10.1016/j.devbrainres.2004.06.004| pmid = 15351500 |first2 = Lucy E.|last2 = Buckby|first3 = Ruth M.|last3 = Empson}}{{Closed access}}</ref><ref name="Strehler">{{cite journal | last1 =Strehler  | first1 =Emanuel E. | title =Role of alternative splicing in generating isoform diversity among plasma membrane calcium pumps| journal =[[Physiol. Rev.]] | volume = 81| issue = 1| pages =21–50 | year =2001 | pmid =11152753 |first2 = David A.|last2 = Zacharias| doi =10.1152/physrev.2001.81.1.21 | s2cid =9062253 }}{{Open access}}</ref>  There is a very large transmembrane [[electrochemical gradient]] of Ca<sup>2+</sup> driving the entry of the [[ion]] into cells, yet it is very important that they maintain low [[concentration]]s of Ca<sup>2+</sup> for proper [[cell signalling]]. Thus, it is necessary for cells to employ [[Ion transporter|ion pump]]s to remove the Ca<sup>2+</sup>.<ref name="Carafoli">{{cite journal | last =Carafoli | first =E. | title =Calcium pump of the plasma membrane | journal =[[Physiol. Rev.]] | volume =71 | issue =1 | pages =129–153 | year =1991 | pmid =1986387 | doi =10.1152/physrev.1991.71.1.129 }}{{Closed access}}</ref>  The PMCA and the [[sodium calcium exchanger]] (NCX) are together the main regulators of [[intracellular space|intracellular]] Ca<sup>2+</sup> concentrations.<ref name="Strehler "/>  Since it transports Ca<sup>2+</sup> into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the [[extracellular space]].<ref name="Talarico">{{cite journal | last1=Talarico | first1=Ernest F. Jr. | title = Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium.| journal =[[Mol. Vis.]] | volume =11 | pages = 169–178| year =2005 | pmid =15765049 | url =http://www.molvis.org/molvis/v11/a19/ | access-date =2013-12-25 |first3 = Carl F.|first2 = Brian G.|last2 = Kennedy|last3 = Marfurt|first4 = Karin U.|last4 = Loeffler|first5 = Nancy J.|last5 = Mangini}}{{Open access}}</ref>
-The PMCA and the [[sodium calcium exchanger]] (NCX) are together the main regulators of [[intracellular space|intracellular]] Ca<sup>2+</sup> concentrations.<ref name="Strehler "/>
-Since it transports Ca<sup>2+</sup> into the extracellular space, the PMCA is also an important regulator of the calcium concentration in the [[extracellular space]].<ref name="Talarico">{{cite journal | last =Talarico Jr | first =EF | authorlink = | coauthors =Kennedy BG; Marfurt CF; Loeffler KU; Mangini NJ | title = Expression and immunolocalization of plasma membrane calcium ATPase isoforms in human corneal epithelium.| journal =Molecular Vision | volume =11 | issue = | pages = 169–178| publisher = | year =2005 | pmid =15765049 | url =http://www.molvis.org/molvis/v11/a19/ | doi = | id = | accessdate = }}</ref>
 PMCAs belong to the family of [[P-type primary ion transport ATPase]]s which form aspartyl phosphate intermediates.<ref name="Strehler "/>
-Various forms of PMCA are expressed in different [[tissue (biology)|tissue]]s, including the [[brain]].<ref name="Jensen06">{{cite journal | last =Jensen  | first =TP | authorlink = | coauthors =Filoteo A; Knopfel T; Empson RM. | title =Pre-synaptic plasma membrane Ca2+ ATPase isoform 2a regulates excitatory synaptic transmission in rat hippocampal CA3 | journal =Journal of Physiology | volume = | issue = | pages =Published online ahead of print | publisher = | year =2006 | url =http://jp.physoc.org/content/579/1/85.full.pdf+html| doi = | id =17170045  | accessdate =2007-01-13 }}</ref>
+Various forms of PMCA are expressed in different [[tissue (biology)|tissue]]s, including the [[brain]].<ref name="Jensen06">{{cite journal | last1 =Jensen  | first1 =Thomas P. | title =Pre-synaptic plasma membrane isoform 2a regulates excitatory synaptic transmission in rat hippocampal CA3 | journal =[[J. Physiol.]] | volume =579 | issue =1 | pages =85–99 | year =2006 | url =http://jp.physoc.org/content/579/1/85.full.pdf+html| doi =10.1113/jphysiol.2006.123901 | access-date =2007-01-13 |pmid = 17170045|first2 = Adelaida G.|last2 = Filoteo|first3 = Thomas|last3 = Knopfel|first4 = Ruth M.|last4 = Empson | pmc=2075377}}{{Open access}}</ref>
 ==Actions==
-The pump is powered by the [[hydrolysis]] of [[adenosine triphosphate]] (ATP), with a [[stoichiometry]] of one Ca<sup>2+</sup> [[ion]] removed for each molecule of ATP hydrolysed.  It binds tightly to Ca<sup>2+</sup> ions (has a high affinity, with a [[Michaelis-Menten kinetics|K<sub>m</sub>]] of 100 to 200 n[[molarity|M]]) but does not remove Ca<sup>2+</sup> at a very fast rate.<ref name="Siegel">{{cite book | last =Siegel | first = GJ| authorlink = | coauthors =Agranoff BW, Albers RW, Fisher SK, Uhler MD, editors | title =Basic Neurochemistry: Molecular, Cellular, and Medical Aspects. 6th ed | publisher =Lippincott,Williams & Wilkins | year = 1999| location =Philadelphia | pages = | url =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 | doi = | id = }} Retrieved on January 13, 2007.</ref>  This is in contrast to the [[sodium calcium exchanger|NCX]], which has a low affinity and a high capacity.  Thus, the PMCA is effective at binding Ca<sup>2+</sup> even when its [[concentration]]s within the cell are very low, so it is suited for maintaining Ca<sup>2+</sup> at its normally very low levels.<ref name="Carafoli"/>  [[Calcium in biology|Calcium]] is an important [[second messenger]], so its levels must be kept low in cells to prevent noise and keep signalling accurate.<ref>{{cite journal | last = Burette | first =A | authorlink = | coauthors =Weinberg RJ | title =Perisynaptic organization of plasma membrane calcium pumps in cerebellar cortex | journal =Journal of Comparative Neurology | volume =500 | issue = 6| pages =1127–1135 | publisher = | year =2007 | url =| doi = 10.1002/cne.21237| pmid =17183553  | accessdate =2007-01-30}}</ref>  The NCX is better suited for removing large amounts of Ca<sup>2+</sup> quickly, as is needed in [[neuron]]s after an [[action potential]].  Thus the activities of the two types of pump complement each other.
+The pump is powered by the [[hydrolysis]] of [[adenosine triphosphate]] (ATP), with a [[stoichiometry]] of one Ca<sup>2+</sup> [[ion]] removed for each molecule of ATP hydrolysed.  It binds tightly to Ca<sup>2+</sup> ions (has a high affinity, with a [[Michaelis-Menten kinetics|K<sub>m</sub>]] of 100 to 200 n[[molarity|M]]) but does not remove Ca<sup>2+</sup> at a very fast rate.<ref name="Siegel">{{cite book | last1 =Albers | first1 = R. Wayne| title =Basic Neurochemistry: Molecular, Cellular, and Medical Aspects | publisher =Lippincott-Raven | year = 1999| location =Philadelphia | pages =<!--not available in online version--> | chapter-url =https://www.ncbi.nlm.nih.gov/books/NBK20385/?term=pmca |edition = 6th|at = ATP-Dependent Ca2+ Pumps|first2 = George J.|last2 = Siegel|chapter = 5. Membrane Transport|access-date = 2013-12-25|editor-last = Siegel|editor-first = George J.|oclc = 39013748|isbn = 978-0-397-51820-3|display-editors=etal}}{{Open access}}</ref>  This is in contrast to the [[sodium calcium exchanger|NCX]], which has a low affinity and a high capacity.  Thus, the PMCA is effective at binding Ca<sup>2+</sup> even when its [[concentration]]s within the cell are very low, so it is suited for maintaining Ca<sup>2+</sup> at its normally very low levels.<ref name="Carafoli"/>  [[Calcium in biology|Calcium]] is an important [[second messenger]], so its levels must be kept low in cells to prevent noise and keep signalling accurate.<ref>{{cite journal | last1 = Burette | first1 =Alain | title =Perisynaptic organization of plasma membrane calcium pumps in cerebellar cortex | journal =[[J. Comp. Neurol.]] | volume =500 | issue = 6| pages =1127–1135 | doi = 10.1002/cne.21237| pmid =17183553  |publication-date = 2006-12-20<!--date of online publication-->|first2 = Richard J.|last2 = Weinberg | date=February 2007| s2cid =22110231 }}{{Closed access}}</ref>  The NCX is better suited for removing large amounts of Ca<sup>2+</sup> quickly, as is needed in [[neuron]]s after an [[action potential]].  Thus the activities of the two types of pump complement each other.
-The PMCA functions in a similar manner to other p-type ion pumps.<ref name="Carafoli"/>  ATP transfers a phosphate to the PMCA, which forms a phosphorylated intermediate.<ref name="Carafoli"/>
+The PMCA functions in a similar manner to other p-type ion pumps.<ref name="Carafoli"/>  ATP transfers a phosphate to the PMCA, which forms a [[protein phosphorylation|phosphorylated]] intermediate.<ref name="Carafoli"/>
 Ca<sup>2+</sup>/[[calmodulin]] binds and further activates the PMCA, increasing the affinity of the protein's Ca<sup>2+</sup>-[[binding site]] 20 to 30 times.<ref name="Siegel"/>  Calmodulin also increases the rate at which the pump extrudes Ca<sup>2+</sup> from the cell, possibly up to tenfold.<ref name="Carafoli"/>
-In brain tissue, it has been postulated that certain types of PMCA are important for regulating [[synapse|synaptic]] activity, since the PMCA is involved in regulating the amount of calcium within the cell at the synapse,<ref name="Jensen06"/> and  Ca<sup>2+</sup> is involved in release of [[synaptic vesicle]]s. Additionally, it has been shown that PMCA activity is modulated and partly powered by [[glycolysis]] in neuronal [[somata]] and [[dendrites]].<ref>{{cite journal | author = Ivannikov, M. et al.| title = Calcium clearance and its energy requirements in cerebellar neurons | journal = Cell Calcium | volume = 47 | issue = 6 | pages = 507–513 | year = 2010 | pmid= 20510449 }}</ref> Presumably, it is due to PMCA proximity to [[glucose transporter]]s in the plasma membrane.
+In brain tissue, it has been postulated that certain types of PMCA are important for regulating [[synapse|synaptic]] activity, since the PMCA is involved in regulating the amount of calcium within the cell at the synapse,<ref name="Jensen06"/> and  Ca<sup>2+</sup> is involved in release of [[synaptic vesicle]]s. Additionally, it has been shown that PMCA activity is modulated and partly powered by [[glycolysis]] in neuronal [[somata]] and [[dendrites]].<ref>{{cite journal | last1 = Ivannikov| title = Calcium clearance and its energy requirements in cerebellar neurons | journal = [[Cell Calcium]] | volume = 47 | issue = 6 | pages = 507–513 | year = 2010 | pmid= 20510449 |first1 = Maxim V.|first2 = Mutsuyuki|last2 = Sugimori|first3 = Rodolfo R.|last3 = Llinás| doi=10.1016/j.ceca.2010.04.004 | pmc=2900537}}{{Closed access}}</ref> Presumably, it is due to PMCA proximity to [[glucose transporter]]s in the plasma membrane.
 ==Structure==
-The structure of the PMCA is similar to that of the [[SERCA]] calcium pumps, which are responsible for removing calcium from the cytoplasm into the lumen of the [[sarcoplasmic reticulum]].<ref name="Strehler "/>  It is thought that the PMCA pump has 10 segments that cross the plasma membrane, with both [[C-terminus|C]] and [[N terminus|N termini]] on the inside of the cell.<ref name="Strehler "/> At the C terminus, there is a long "tail" of between 70 and 200 [[amino acid]]s in length.<ref name="Strehler "/> This tail is thought to be responsible for regulation of the pump.<ref name="Strehler "/>
+The structure of the PMCA is similar to that of the [[SERCA]] calcium pumps, which are responsible for removing calcium from the cytoplasm into the lumen of the [[sarcoplasmic reticulum]].<ref name="Strehler "/> Calcium tends to have a slightly lower [[Ligand (biochemistry)|affinity]] for PMCA pumps than for SERCA pumps.<ref>{{Citation|last1=Lopez|first1=Jose R.|title=Chapter 56 - Control of Resting Ca2+ Concentration in Skeletal Muscle|date=2012-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780123815101000569|work=Muscle|pages=801–810|editor-last=Hill|editor-first=Joseph A.|place=Boston/Waltham|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-381510-1.00056-9|isbn=978-0-12-381510-1|access-date=2020-11-08|last2=Allen|first2=Paul D.|editor2-last=Olson|editor2-first=Eric N.}}</ref> It is thought that the PMCA pump has 10 segments that cross the plasma membrane, with both [[C-terminus|C]] and [[N terminus|N termini]] on the inside of the cell.<ref name="Strehler "/> At the C terminus, there is a long "tail" of between 70 and 200 [[amino acid]]s in length.<ref name="Strehler "/> This tail is thought to be responsible for regulation of the pump.<ref name="Strehler "/> PMCA pumps have a molecular mass of around 140 [[Dalton (unit)|kDa]].<ref>{{Citation|last1=Edes|first1=Istvan|title=13 - Ca2+-ATPases|date=1995-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780126569704500191|work=Cell Physiology Source Book|pages=156–165|editor-last=Sperelakis|editor-first=NICHOLAS|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-656970-4.50019-1|isbn=978-0-12-656970-4|access-date=2020-11-08|last2=Kranias|first2=Evangelia G.}}</ref>
 ==Isoforms==
@@ Line 33: / Line 31: @@
 Each  isoform is coded by a different gene and is expressed in different areas of the body.<ref name="Jensen06"/> [[Alternate splicing]] of the [[mRNA]] transcripts of these genes results in different subtypes of these isoforms.<ref name="Strehler "/> Over 20 splice variants have been identified so far.<ref name="Strehler "/>
-Three PMCA isoforms, PMCA1, PMCA2, and PMCA3, occur in the [[brain]] in varying distributions.<ref name="Siegel"/>  PMCA1 is ubiquitous throughout all [[tissue (biology)|tissue]]s in humans, and without it [[embryo]]s do not survive.<ref name="Talarico"/> Lack of PMCA4, which is also very common in many tissues, is survivable, but leads to [[infertility]] in males.<ref name="Talarico"/>  PMCA types 2 and 3 are activated more quickly and are, therefore, better suited to excitable cell types such as those in nervous and muscle tissue, which experiences large influxes of Ca<sup>2+</sup> when excited.<ref name="Jensen06"/>  PMCA types 1, 2, and 4 have been found in [[glial cell]]s called [[astrocyte]]s in mammals, though it was previously thought that only the NCX was present in glia.<ref name="Fresu ">{{cite journal | last =Fresu  | first =L | authorlink = | coauthors =  Dehpour A, Genazzani AA, Carafoli E, Guerini D | title =Plasma membrane calcium ATPase isoforms in astrocytes | journal =Glia | volume = 28| issue = 2| pages =150–155 | publisher = | year =1999  | url = | doi = 10.1002/(SICI)1098-1136(199911)28:2<150::AID-GLIA6>3.0.CO;2-7| pmid =10533058  | accessdate =2007-01-30 }}</ref>  Astrocytes help to maintain ionic balance in the [[extracellular space]] in the brain.
+Three PMCA isoforms, PMCA1, PMCA2, and PMCA3, occur in the [[brain]] in varying distributions.<ref name="Siegel"/>  PMCA1 is ubiquitous throughout all [[tissue (biology)|tissue]]s in humans, and without it [[embryo]]s do not survive.<ref name="Talarico"/> Lack of PMCA4, which is also very common in many tissues, is survivable, but leads to [[infertility]] in males.<ref name="Talarico"/>  PMCA types 2 and 3 are activated more quickly and are, therefore, better suited to excitable cell types such as those in nervous and muscle tissue, which experiences large influxes of Ca<sup>2+</sup> when excited.<ref name="Jensen06"/>  PMCA types 1, 2, and 4 have been found in [[glial cell]]s called [[astrocyte]]s in mammals, though it was previously thought that only the NCX was present in glia.<ref name="Fresu">{{cite journal | last1 =Fresu  | first1 =Luigia | title =Plasma membrane calcium ATPase isoforms in astrocytes | journal =[[Glia (journal)|Glia]] | volume = 28| issue = 2| pages =150–155 | doi = 10.1002/(SICI)1098-1136(199911)28:2<150::AID-GLIA6>3.0.CO;2-7| pmid =10533058  |publication-date = 1999-10-22<!--date of online publication-->|first2 = Ahmed|last2 = Dehpour|first3 = Armando A.|last3 = Genazzani|first4 = Ernesto|last4 = Carafoli|first5 = Danilo|last5 = Guerini | date=November 1999| s2cid =44343760 | doi-access = free}}{{Closed access}}</ref>  Astrocytes help to maintain ionic balance in the [[extracellular space]] in the brain.
-[[Gene knockout|Knock-out]] of PMCA2 causes [[inner ear]] problems, including [[hearing loss]] and problems with [[Equilibrioception|balance]].<ref name="Schuh ">{{cite journal | last =Schuh  | first =K | authorlink = | coauthors = Uldrijan S, Telkamp M, Rothlein N, Neyses L| title = The plasmamembrane calmodulin–dependent calcium pump : a major regulator of nitric oxide synthase I| journal =Journal of Cell Biology | volume =155 | issue =2 | pages =201–205 | publisher = The Rockefeller University Press| year =2001 | url =http://www.jcb.org/cgi/content/full/155/2/201 | doi=  10.1083/jcb.200104131| pmc =2198825 | pmid =11591728  | accessdate =2007-01-30 }}</ref>
+[[Gene knockout|Knock-out]] of PMCA2 causes [[inner ear]] problems, including [[hearing loss]] and problems with [[Equilibrioception|balance]].<ref name="Schuh">{{cite journal | last1 =Schuh  | first1 =Kai | title = The plasmamembrane calmodulin–dependent calcium pump : a major regulator of nitric oxide synthase I| journal =[[J. Cell Biol.]] | volume =155 | issue =2 | pages =201–205 | year =2001 | doi=  10.1083/jcb.200104131| pmc =2198825 | pmid =11591728  |first2 = Stjepan|last2 = Uldrijan|first3 = Myriam|last3 = Telkamp|first4 = Nicola|last4 = Röthlein|first5 = Ludwig|last5 = Neyses}}{{Open access}}</ref>
 PMCA4 exists in [[caveolae]].<ref name="Schuh "/> Isoform PMCA4b interacts with [[nitric oxide synthase]] and reduces synthesis of [[nitric oxide]] by that [[enzyme]].<ref name="Schuh "/>
-PMCA isoform 4 has a molecular weight of 134,683, calculated from its sequence.<ref>{{cite journal | last =Verma| first = AK| authorlink = | coauthors =Filoteo AG, Stanford DR, Wieben ED, Penniston JT, Strehler EE, Fischer R, Heim R, Vogel G, Mathews S, Strehler-Page M-A, James P, Vorherr T, Krebs J, Carafoli E | title =Complete Primary Structure of a Human Plasma Membrane Ca<sup>2+</sup> Pump. | journal = The Journal of Biological Chemistry | volume =263| issue =28 | pages =14152–14159 | publisher = | year =1988 | url = http://www.jbc.org/| doi = | pmid = 2844759| accessdate =2008-09-01}}</ref> This is in good agreement with the results of SDS gel electrophoresis.<ref>{{cite journal | last =Graf| first = E| authorlink = | coauthors =Verma, AK, Gorski, JP, Lopaschuk, G, Niggli, V, Zurini, M, Carafoli, E, Penniston, JT | title =Molecular Properties of Calcium-Pumping ATPase from Human Erythrocytes. | journal = Biochemistry| volume =21| issue = 18| pages =4511–4516| publisher = | year =1982| url = http://acsinfo.acs.org/journals/bichaw/bichaw.html| doi = 10.1021/bi00261a049| pmid = 6215062| accessdate =2008-09-01 | format = &ndash; <sup>[http://scholar.google.co.uk/scholar?hl=en&lr=&q=author%3AGraf+intitle%3AMolecular+Properties+of+Calcium-Pumping+ATPase+from+Human+Erythrocytes.&as_publication=Biochemistry&as_ylo=&as_yhi=&btnG=Search Scholar search]</sup>}} {{dead link|date=February 2009}}</ref>
+PMCA isoform 4 has a molecular weight of 134,683, calculated from its sequence.<ref>{{cite journal | last1 =Verma| first1 = Anil K.| title =Complete Primary Structure of a Human Plasma Membrane Ca<sup>2+</sup> Pump. | journal = [[J. Biol. Chem.]] | volume =263| issue =28 | pages =14152–14159 | year =1988 | url = http://www.jbc.org/content/263/28/14152.abstract| pmid = 2844759| access-date =2013-12-25|first2 = Adelaida G.|last2 = Filoteo|first3 = David R.|last3 = Stanford|first4 = Eric D.|last4 = Wieben|first5 = John T.|last5 = Penniston| doi = 10.1016/S0021-9258(18)68198-0| doi-access = free}}{{Open access}}</ref> This is in good agreement with the results of SDS gel electrophoresis.<ref>{{cite journal | last1 =Graf| first1 = Ernst| title =Molecular Properties of Calcium-Pumping ATPase from Human Erythrocytes | journal = [[Biochemistry (journal)|Biochemistry]]| volume =21| issue = 18| pages =4511–4516| year =1982| doi = 10.1021/bi00261a049| pmid = 6215062|first2 = Anil K.|last2 = Verma|first3 = Jeffrey P.|last3 = Gorski|first4 = Gary|last4 = Lopaschuk|first5 = Verena|last5 = Niggli|first6 = Mauro|last6 = Zurini|first7 = E.|last7 = Carafoli|first8 = John T.|last8 = Penniston}}{{Closed access}}</ref>
 ==Pathology==
-When the PMCA fails to function properly, disease can result.  Improperly functioning PMCA proteins have been found associated with conditions such as [[sensorineural deafness]], [[diabetes]], and [[hypertension]].<ref name="Talarico"/>
+When the PMCA fails to function properly, disease can result. Improperly functioning PMCA proteins have been found associated with conditions such as [[sensorineural deafness]], [[diabetes]], and [[hypertension]].<ref name="Talarico"/>
 In [[excitotoxicity]], a process in which excessive amounts of the [[neurotransmitter]] [[glutamate]] overactivate [[neuron]]s, resulting in excessive influx of Ca<sup>2+</sup> into cells, the activity of the PMCA may be insufficient to remove the excess Ca<sup>2+</sup>.
-In [[breast]] tissue, mammary epithelial cells express PMCA2, which transports calcium across the apical surface of the cells into milk. PMCA2 expression falls on weaning, leading to calcium-induced [[apoptosis]] and mammary gland involution. Persistent PMCA2 expression in certain [[breast cancer]]s lowers calcium levels inside malignant cells, allowing them to avoid apoptosis. These tumors are also usually positive for the HER2 protein, tend to involve the lymph nodes, and are more common among young women, which could help explain their worse prognosis compared with postmenopausal women.<ref>VanHouten, J. et al. “PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer.” Proceedings of the National Academy of Sciences 107.25 (2010) : 11405-11410. 10 Feb 2011.</ref>
+In [[breast]] tissue, mammary [[Epithelium|epithelial cells]] express PMCA2, which transports calcium across the [[Cell membrane|apical surface]] of the cells into [[Breast milk|milk]]. PMCA2 expression falls on [[weaning]], leading to calcium-induced [[apoptosis]] and [[Involution (medicine)|mammary gland involution]]. Persistent PMCA2 expression in certain [[breast cancer]]s lowers calcium levels inside malignant cells, allowing them to avoid apoptosis. These tumors are also usually positive for the [[HER2/neu|HER2 protein]], tend to involve the [[Lymph node|lymph nodes]], and are more common among young women, which could help explain their worse prognosis compared with postmenopausal women.<ref>{{Cite journal|title = PMCA2 regulates apoptosis during mammary gland involution and predicts outcome in breast cancer|journal = [[Proc. Natl. Acad. Sci. U.S.A.]]|doi = 10.1073/pnas.0911186107|pmid = 20534448|volume = 107|issue = 25|pages = 11405–11410|publication-date = 2010-06-04<!--published online-->|first1 = Joshua|last1 = VanHouten|first2 = Catherine|last2 = Sullivan|first3 = Caroline|last3 = Bazinet|first4 = Tom|last4 = Ryoo|first5 = Robert|last5 = Camp|first6 = David L.|last6 = Rimm|first7 = Gina|last7 = Chung|first8 = John|last8 = Wysolmerski|pmc = 2895115|date = 2010-06-22|bibcode = 2010PNAS..10711405V|doi-access = free}}{{Open access}}</ref>
+[[Curcumin]] can bind to the PMCA, inducing a [[conformational change]] that prevents [[Adenosine triphosphate|ATP]] from binding.<ref>{{Citation|last1=Shehzad|first1=Adeeb|title=Chapter Eight - Curcumin: A Potent Modulator of Multiple Enzymes in Multiple Cancers|date=2014-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780128022153000082|journal=The Enzymes|volume=36|pages=149–174|editor-last=Bathaie|editor-first=S. Zahra|series=Natural Products and Cancer Signaling: Isoprenoids, Polyphenols and Flavonoids|publisher=Academic Press|language=en|doi=10.1016/b978-0-12-802215-3.00008-2|access-date=2020-11-08|last2=Shahzad|first2=Raheem|last3=Lee|first3=Young Sup|pmid=27102703|editor2-last=Tamanoi|editor2-first=Fuyuhiko}}</ref>
 ==History==
-PMCAs were first discovered in the 1960s in the membranes of [[red blood cell]]s.<ref name="Strehler "/> The presence of an ATPase was discovered in the membranes in 1961, and then in 1966 it was discovered that these ATPases pump Ca<sup>2+</sup> out of the [[cytosol]].<ref name="Carafoli"/>
+PMCAs were first discovered in the 1960s in the membranes of [[red blood cell]]s.<ref name="Strehler "/> The presence of an [[ATPase]] was discovered in the membranes in 1961, and then in 1966 it was discovered that these ATPases pump Ca<sup>2+</sup> out of the [[cytosol]].<ref name="Carafoli"/>
-PMCA was first purified from red blood cell membranes in 1979.<ref>{{cite journal | last =Niggli| first = V| authorlink = | coauthors =Penniston JT, Carafoli E | title =Purification of the (Ca<sup>2+</sup>-Mg<sup>2+</sup> ATPase from Human Erythrocyte Membranes using a Calmodulin Affinity Column. | journal = The Journal of Biological Chemistry | volume =254| issue =20 | pages =9955–9958| publisher = | year =1979 | url = http://www.jbc.org/| doi = | pmid = 158595| accessdate =2008-09-01}}.
+PMCA was first purified from red blood cell membranes in 1979.<ref>{{cite journal | last1 =Niggli| first1 = Verena| title =Purification of the (Ca<sup>2+</sup>-Mg<sup>2+</sup>) ATPase from Human Erythrocyte Membranes using a Calmodulin Affinity Column. | journal = [[J. Biol. Chem.]] | volume =254| issue =20 | pages =9955–9958| year =1979 | url = http://www.jbc.org/| pmid = 158595| access-date =2013-12-25|first2 = John T.|last2 = Penniston|first3 = Ernesto|last3 = Carafoli| doi = 10.1016/S0021-9258(19)86652-8| doi-access = free}}{{Open access}}.
+</ref><ref>{{cite book | last1 =Penniston| first1 = John T. | volume =157| issue =27 | pages =340–351| year =1988| doi = 10.1016/0076-6879(88)57089-1| pmid = 2976465|first2 = Adelaida|last2 = Gfiloteo|first3 = Carol S.|last3 = McDonough|first4 = Ernesto|last4 = Carafoli| title = Biomembranes Part Q: ATP-Driven Pumps and Related Transport: Calcium, Proton, and Potassium Pumps | chapter = Purification, reconstitution, and regulation of plasma membrane Ca<sub>2</sub><sup>+</sup>-pumps| series = Methods in Enzymology | isbn = 978-0-12-182058-9}}{{Closed access}}.</ref>
-</ref><ref>{{cite journal | last =Penniston| first = JT| authorlink = | coauthors = Filoteo AG, McDonough CS, Carafoli E | title =Purification Reconstitution and Regulation of Plasma Membrane Ca<sup>2+</sup> Pumps. | journal = Methods in Enzymology| volume =157| issue = | pages =340–351| publisher = | year =1988| url = http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B7CV2-4B42SFD-39&_user=10&_coverDate=12%2F31%2F1988&_rdoc=31&_fmt=high&_orig=browse&_srch=doc-info(%23toc%2318066%231988%23998429999%23472660%23FLA%23display%23Volume)&_cdi=18066&_sort=d&_docanchor=&_ct=60&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=682083542638dd06234e5a1d7b4bacfc| doi = 10.1016/0076-6879(88)57089-1| pmid = 2976465| accessdate =2008-09-01}}.</ref>
 ==References==
@@ Line 63: / Line 63: @@
 {{ATPases}}
-[[Category:Transport proteins]]
+[[Category:Transmembrane transporters]]