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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.^[1] Failure to do so is one cause of muscle cramps.

The plasma membrane Ca²⁺ ATPase and the sodium-calcium exchanger are together the main regulators of cytoplasmic Ca²⁺ concentrations.^[2]

Biological role

Ca²⁺ has many important roles as an intracellular messenger. The release of a large amount of free Ca²⁺ can trigger a fertilized egg to develop, skeletal muscle cells to contract, secretion by secretory cells and interactions with Ca²⁺ -responsive proteins like calmodulin.^[3] To maintain low concentrations of free Ca²⁺ in the cytosol, cells use membrane pumps like calcium ATPase found in the membranes of sarcoplasmic reticulum of skeletal muscle. These pumps are needed to provide the steep electrochemical gradient that allows Ca²⁺ to rush into the cytosol when a stimulus signal opens the Ca²⁺ channels in the membrane. The pumps are also necessary to actively pump the Ca²⁺ back out of the cytoplasm and return the cell to its pre-signal state.^[3]

Crystallography of calcium pumps

The structure of calcium pumps found in the sarcoplasmic reticulum of skeletal muscle was elucidated in 2000 by Toyoshima, et al. using microscopy of tubular crystals and 3D microcrystals. The pump has a molecular mass of 110,000 amu, shows three well separated cytoplasmic domains, with a transmembrane domain consisting of ten alpha helices and two transmembrane Ca²⁺ binding sites.^[4]

Mechanism

Classical theory of active transport for P-type ATPases ^[5]

E1 →	(2H⁺ out, 2Ca²⁺ in)→	E1⋅2Ca²⁺ →	E1⋅ ATP
↑			↓
E2			E1⋅ADP
↑(Pi out)			↓(ADP out)
E2⋅Pi	← E2P	←(2H⁺ in, 2Ca²⁺ out)	← E1P

Data from crystallography studies by Chikashi Toyoshima applied to the above cycle ^[6]^[7]

E1 - high affinity for Ca²⁺, 2 Ca²⁺ bound, 2 H⁺ counter ions released
E1⋅2Ca²⁺ - cytoplasmic gate open, free Ca²⁺ ion exchange occurs between bound ions and those in cytoplasm, closed configuration of N, P, A domains broken, exposing catalytic site
E1⋅ ATP - ATP binds and links N to P, P bends, N contacts A, A causes M1 helix to pull up, closes cytoplasmic gate, bound Ca²⁺ occluded in transmembrane
E1⋅ADP - Phosphoryl transfer, ADP dissociates
E1P - A rotates, transmembrane helices rearrange, binding sites destroyed, lumenal gate opened, bound Ca²⁺ released
E2P - open ion pathway to lumen, Ca²⁺ to lumen
E2⋅Pi - A catalyzes release of the Pi, P unbends, transmembrane helices rearranged, closes lumenal gate
E2 - transmembrane M1 forms cytoplasmic access tunnel to Ca²⁺ binding sites

References

^ Carafoli E (January 1991). "Calcium pump of the plasma membrane". Physiol. Rev. 71 (1): 129–53. doi:10.1152/physrev.1991.71.1.129. PMID 1986387.
^ Strehler EE, Zacharias DA (January 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 Alberts, Bruce; Bray, Dennis; Hopkin, Karen; Johnson, Alexander D; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2009). Essential Cell Biology (3rd ed.). New York: Garland Science. pp. 552–554. ISBN 978-0815341291.
^ Toyoshima, Chikashi; Nakasako, Masayoshi; Nomura, Hiromi; Ogawa, Haruo (8 June 2000). "Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 Å resolution". Nature. 405 (6787): 647–655. Bibcode:2000Natur.405..647T. doi:10.1038/35015017. PMID 10864315. S2CID 4316039.
^ Toyoshima, Chikashi; Norimatsu, Yoshiyuki; Iwasawa, Shiho; Tsuda, Takeo; Ogawa, Haruo (5 December 2007). "How processing of aspartylphosphate is coupled to lumenal gating of the ion pathway in the calcium pump". Proceedings of the National Academy of Sciences. 104 (50): 19831–19836. Bibcode:2007PNAS..10419831T. doi:10.1073/pnas.0709978104. PMC 2148383. PMID 18077416.
^ Toyoshima, Chikashi; Nomura, Hiromi (8 August 2002). "Structural changes in the calcium pump accompanying the dissociation of calcium". Nature. 418 (6898): 605–611. Bibcode:2002Natur.418..605T. doi:10.1038/nature00944. PMID 12167852. S2CID 1441673.
^ Toyoshima, Chikashi; Mizutani, Tatsuaki (30 June 2004). "Crystal structure of the calcium pump with a bound ATP analogue". Nature. 430 (6999): 529–535. Bibcode:2004Natur.430..529T. doi:10.1038/nature02680. PMID 15229613. S2CID 4331138.