Calcineurin

Protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform, also known as PPP3CA, is a human gene.cite web | title = Entrez Gene: PPP3CA protein phosphatase 3 (formerly 2B), catalytic subunit, alpha isoform| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5530| accessdate = ]

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 Nuclear factor of activated T cell, cytoplasmic component (NFATc), a transcription factor that can then go into the nucleus and turn on genes involved in IL-2 synthesis.

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 [ [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2213529 T Cell Receptor–Induced Calcineurin Activation Regulates T Helper Type 2 Cell Development by Modifying the Interleukin 4 Receptor Signaling Complex] ] 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.

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. [ [http://web.mit.edu/newsoffice/2003/mice.html MIT research may lead to better schizophrenia drugs - MIT News Office ] ]

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. [ [http://news.bbc.co.uk/1/hi/health/5363150.stm BBC NEWS | Health | Hope for new diabetes treatment ] ] [ [http://www.eurekalert.org/pub_releases/2006-09/sumc-hfs091406.php Hope for significant new diabetes treatment in Stanford discovery ] ]

Calcineurin/Nfat signaling is required for perinatal lung maturation and function: [ [http://www.eurekalert.org/pub_releases/2006-09/joci-chn091406.php Calcineurin helps newborns breathe easy ] ]

References

Further reading

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

External links

*
*

PBB_Controls
update_page = yes
require_manual_inspection = no
update_protein_box = yes
update_summary = yes
update_citations = yes