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Calcineurin: Wikis


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From Wikipedia, the free encyclopedia

Protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform

PDB rendering based on 1aui.
Available structures
1aui, 1m63, 1mf8, 1tco, 2jog, 2p6b
External IDs OMIM114105 MGI107164 HomoloGene55497 GeneCards: PPP3CA Gene
RNA expression pattern
PBB GE PPP3CA 202429 s at tn.png
PBB GE PPP3CA 202425 x at tn.png
PBB GE PPP3CA 202457 s at tn.png
More reference expression data
Species Human Mouse
Entrez 5530 19055
Ensembl ENSG00000138814 ENSMUSG00000028161
UniProt Q08209 P63328
RefSeq (mRNA) NM_000944 NM_008913
RefSeq (protein) NP_000935 NP_032939
Location (UCSC) Chr 4:
102.16 - 102.49 Mb
Chr 3:
136.61 - 136.87 Mb
PubMed search [1] [2]

Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and formerly known as protein phosphatase 2B (PP2B).[1] It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates NFATc (Nuclear Factor of Activated T cell, cytoplasmic), a transcription factor by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporin, pimecrolimus and tacrolimus.


Mechanism of action

When an antigen-presenting cell interacts with a T cell receptor on T cells, there is an increase in the cytoplasmic level of calcium, which[2] activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NFATs) that are important in the transcription of IL-2 genes. IL-2 activates T-helper lymphocytes and induces the production of other cytokines. In this way, it governs the action of cytotoxic lymphocytes and NK cells. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.

Clinical significance


Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA[3]. An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans with schizophrenia: impairment in working memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia.[4]


Scientists believe that calcineurin might prove to be one of the two keys, along with NFAT, in improving the function of diabetics' pancreatic beta cells.[5][6]

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.[7]


Calcineurin has been shown to interact with DSCR1[8] and AKAP5.[9]


  1. ^ "Entrez Gene: PPP3CA protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform".  
  2. ^ Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C, Kamata T, Shin T, Seki N, Suzuki S, Taniguchi M, Nakayama T (June 2000). "T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex". J. Exp. Med. 191 (11): 1869–79. doi:10.1084/jem.191.11.1869. PMID 10839803.  
  3. ^ Bannai, H., Levi, S., Schweizer, C., Inoue, T., Launey, T., Racine, V., et al. (2009). Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron, 62(5), 670-682.
  4. ^ Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S (July 2003). "Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8987–92. doi:10.1073/pnas.1432926100. PMID 12851457.  
  5. ^ Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK (September 2006). "Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function". Nature 443 (7109): 345–9. doi:10.1038/nature05097. PMID 16988714.  
  6. ^ Heit JJ (October 2007). "Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics". Bioessays 29 (10): 1011–21. doi:10.1002/bies.20644. PMID 17876792.  
  7. ^ Davé V, Childs T, Xu Y, Ikegami M, Besnard V, Maeda Y, Wert SE, Neilson JR, Crabtree GR, Whitsett JA (October 2006). "Calcineurin/Nfat signaling is required for perinatal lung maturation and function". J. Clin. Invest. 116 (10): 2597–609. doi:10.1172/JCI27331. PMID 16998587.  
  8. ^ Fuentes, J J; Genescà L, Kingsbury T J, Cunningham K W, Pérez-Riba M, Estivill X, de la Luna S (Jul. 2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. (ENGLAND) 9 (11): 1681–90. ISSN 0964-6906. PMID 10861295.  
  9. ^ Kashishian, A; Howard M, Loh C, Gallatin W M, Hoekstra M F, Lai Y (Oct. 1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. (UNITED STATES) 273 (42): 27412–9. ISSN 0021-9258. PMID 9765270.  

Further reading

  • Crabtree GR (1999). "Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT". Cell 96 (5): 611–4. doi:10.1016/S0092-8674(00)80571-1. PMID 10089876.  
  • Giri PR, Higuchi S, Kincaid RL (1992). "Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit". Biochem. Biophys. Res. Commun. 181 (1): 252–8. doi:10.1016/S0006-291X(05)81410-X. PMID 1659808.  
  • Kincaid RL, Giri PR, Higuchi S, et al. (1990). "Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods". J. Biol. Chem. 265 (19): 11312–9. PMID 2162844.  
  • Guerini D, Klee CB (1990). "Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain". Proc. Natl. Acad. Sci. U.S.A. 86 (23): 9183–7. doi:10.1073/pnas.86.23.9183. PMID 2556704.  
  • Kincaid RL, Nightingale MS, Martin BM (1988). "Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin". Proc. Natl. Acad. Sci. U.S.A. 85 (23): 8983–7. doi:10.1073/pnas.85.23.8983. PMID 2848250.  
  • Coghlan VM, Perrino BA, Howard M, et al. (1995). "Association of protein kinase A and protein phosphatase 2B with a common anchoring protein". Science 267 (5194): 108–11. doi:10.1126/science.7528941. PMID 7528941.  
  • Griffith JP, Kim JL, Kim EE, et al. (1995). "X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex". Cell 82 (3): 507–22. doi:10.1016/0092-8674(95)90439-5. PMID 7543369.  
  • Shibasaki F, McKeon F (1995). "Calcineurin functions in Ca(2+)-activated cell death in mammalian cells". J. Cell Biol. 131 (3): 735–43. doi:10.1083/jcb.131.3.735. PMID 7593193.  
  • Muramatsu T, Kincaid RL (1993). "Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha)". Biochim. Biophys. Acta 1178 (1): 117–20. doi:10.1016/0167-4889(93)90117-8. PMID 8392375.  
  • Cameron AM, Steiner JP, Roskams AJ, et al. (1996). "Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux". Cell 83 (3): 463–72. doi:10.1016/0092-8674(95)90124-8. PMID 8521476.  
  • Kissinger CR, Parge HE, Knighton DR, et al. (1996). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. doi:10.1038/378641a0. PMID 8524402.  
  • Wang MG, Yi H, Guerini D, et al. (1997). "Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21→q22 and 2p16→p15 respectively". Cytogenet. Cell Genet. 72 (2-3): 236–41. doi:10.1159/000134198. PMID 8978785.  
  • Shibasaki F, Kondo E, Akagi T, McKeon F (1997). "Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2". Nature 386 (6626): 728–31. doi:10.1038/386728a0. PMID 9109491.  
  • Kashishian A, Howard M, Loh C, et al. (1998). "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. doi:10.1074/jbc.273.42.27412. PMID 9765270.  
  • Wang HG, Pathan N, Ethell IM, et al. (1999). "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science 284 (5412): 339–43. doi:10.1126/science.284.5412.339. PMID 10195903.  
  • Fuentes JJ, Genescà L, Kingsbury TJ, et al. (2000). "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. doi:10.1093/hmg/9.11.1681. PMID 10861295.  
  • Hartley JL, Temple GF, Brasch MA (2001). "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. doi:10.1101/gr.143000. PMID 11076863.  
  • Frey N, Richardson JA, Olson EN (2001). "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14632–7. doi:10.1073/pnas.260501097. PMID 11114196.  
  • Siddiq A, Miyazaki T, Takagishi Y, et al. (2001). "Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism". Endocrinology 142 (5): 1752–9. doi:10.1210/en.142.5.1752. PMID 11316738.  

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