Calcineurin

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
Identifiers
Symbol(s) PPP3CA; CCN1; CNA1; CALN; CALNA; CALNA1; PPP2B
External IDs OMIM: 114105 MGI: 107164 HomoloGene: 55497
RNA expression pattern

More reference expression data
Orthologs
Human Mouse
Entrez 5530 19055
Ensembl ENSG00000138814 ENSMUSG00000028161
Uniprot Q08209 P63328
Refseq NM_000944 (mRNA)
NP_000935 (protein)		 NM_008913 (mRNA)
NP_032939 (protein)
Location Chr 4: 102.16 - 102.49 Mb Chr 3: 136.61 - 136.87 Mb
Pubmed search [1] [2]

Protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform, also known as PPP3CA, is a human gene.[1]

Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 2B (PP2B). Calcineurin is responsible for activating the transcription of interleukin 2 (IL-2), that stimulates the growth and differentiation of T cell response. In immunosuppressive therapy it is inhibited by cyclosporin, pimecrolimus (Elidel) and tacrolimus (FK506) - these drugs are known as calcineurin inhibitors. Calcineurin dephosphorylates NFATc, a transcription factor that can then go into the nucleus and turn on genes involved in IL-2 synthesis.

Contents

[edit] Mechanism of action

When a B cell receptor interacts with an antigen, the intracellular concentration of calcium rises. This increase activates calcineurin, by binding a regulatory subunit and activating calmodulin binding. Calcineurin induces different transcription factors (NF-ATs) 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.

[edit] Research into Schizophrenia

Calcineurin is linked to receptors for two brain chemicals, NMDA and dopamine. An MIT 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.[2]

[edit] Research into Diabetes

Scientist believe that calcineurin might prove to be one of the two keys, along with NFAT, in improving the function of diabetics' pancreatic beta cells.[3][4]

Calcineurin/Nfat signaling is required for perinatal lung maturation and function:[5]

[edit] References

  1. ^ Entrez Gene: PPP3CA protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform.
  2. ^ MIT research may lead to better schizophrenia drugs - MIT News Office
  3. ^ BBC NEWS | Health | Hope for new diabetes treatment
  4. ^ Hope for significant new diabetes treatment in Stanford discovery
  5. ^ Calcineurin helps newborns breathe easy

[edit] 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. 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. 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. 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. 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. 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. 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. 

[edit] External links

 This hydrolase article is a stub. You can help Wikipedia by expanding it.
v • d • e
Hydrolase: esterases (EC 3.1)
3.1.1: Carboxylic ester hydrolases
3.1.2: Thioesterase
3.1.3: Phosphatase
3.1.4: Phosphodiesterase
3.1.6: Sulfatase
other
Languages