Biology:Calcineurin
Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase).[2] It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), 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 the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus.
Structure
Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca2+-binding regulatory subunit, calcineurin B. There are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA, PPP3CB, and PPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1, PPP3R2).
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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 activates calcineurin by binding a regulatory subunit and activating calmodulin binding.[3] Calcineurin induces 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. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.
Clinical relevance
Rheumatic diseases
Calcineurin inhibitors are prescribed for adult rheumatoid arthritis (RA) as a single drug or in combination with methotrexate. The microemulsion formulation is approved by the U.S. Food and Drug Administration for treatment of severely active RA. It is also prescribed for: psoriatic arthritis, psoriasis, acute ocular Behçet's disease, juvenile idiopathic arthritis, adult and juvenile polymyositis and dermatomyositis, adult and juvenile systemic lupus erythematosus, adult lupus membranous nephritis, systemic sclerosis, aplastic anemia, steroid-resistant nephrotic syndrome, atopic dermatitis, severe corticosteroid-dependent asthma, severe ulcerative colitis, pemphigus vulgaris, myasthenia gravis, and dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion).[4]
Schizophrenia
Calcineurin is linked to receptors for several brain chemicals including glutamate, dopamine and GABA.[5] 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.[6]
Diabetes
Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells.[7][8] Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation.[9]
Calcineurin/NFAT signaling is required for perinatal lung maturation and function.[10]
Organ transplantation
Calcineurin inhibitors such as tacrolimus are used to suppress the immune system in organ allotransplant recipients to prevent rejection of the transplanted tissue.[11]
Interactions
Calcineurin has been shown to interact with RCAN1[12] and AKAP5.[13]
References
- ↑ PDB: 1AUI; "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. December 1995. doi:10.1038/378641a0. PMID 8524402. Bibcode: 1995Natur.378..641K.
- ↑ "Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis". Mol. Biol. Rep. 32 (1): 41–5. March 2005. doi:10.1007/s11033-004-4250-4. PMID 15865209.
- ↑ "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. June 2000. doi:10.1084/jem.191.11.1869. PMID 10839803.
- ↑ "Pharmacology and side effects of cyclosporine and tacrolimus". 2014-04-10. http://www.uptodate.com/contents/pharmacology-and-side-effects-of-cyclosporine-and-tacrolimus.
- ↑ "Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics". Neuron 62 (5): 670–82. 2009. doi:10.1016/j.neuron.2009.04.023. PMID 19524526.
- ↑ "Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia". Proc. Natl. Acad. Sci. U.S.A. 100 (15): 8987–92. July 2003. doi:10.1073/pnas.1432926100. PMID 12851457. Bibcode: 2003PNAS..100.8987M.
- ↑ "Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function". Nature 443 (7109): 345–9. September 2006. doi:10.1038/nature05097. PMID 16988714. Bibcode: 2006Natur.443..345H.
- ↑ "Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics". BioEssays 29 (10): 1011–21. October 2007. doi:10.1002/bies.20644. PMID 17876792.
- ↑ "Transplant-associated hyperglycemia: a new look at an old problem". Clin J Am Soc Nephrol 2 (2): 343–55. 2007. doi:10.2215/CJN.03671106. PMID 17699434.
- ↑ "Calcineurin/Nfat signaling is required for perinatal lung maturation and function". J. Clin. Invest. 116 (10): 2597–609. October 2006. doi:10.1172/JCI27331. PMID 16998587.
- ↑ "Tacrolimus". 1 March 2019. https://www.nzf.org.nz/nzf_4754.
- ↑ "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. July 2000. doi:10.1093/hmg/9.11.1681. PMID 10861295.
- ↑ "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. October 1998. doi:10.1074/jbc.273.42.27412. PMID 9765270.
Further reading
- "Working memory impairment in calcineurin knock-out mice is associated with alterations in synaptic vesicle cycling and disruption of high-frequency synaptic and network activity in prefrontal cortex". J. Neurosci. 33 (27): 10938–49. July 2013. doi:10.1523/JNEUROSCI.5362-12.2013. PMID 23825400.
- "Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT". Cell 96 (5): 611–4. 1999. doi:10.1016/S0092-8674(00)80571-1. PMID 10089876.
- "Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit". Biochem. Biophys. Res. Commun. 181 (1): 252–8. 1991. doi:10.1016/S0006-291X(05)81410-X. PMID 1659808.
- "Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods". J. Biol. Chem. 265 (19): 11312–9. 1990. doi:10.1016/S0021-9258(19)38593-X. PMID 2162844.
- "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. 1989. doi:10.1073/pnas.86.23.9183. PMID 2556704. Bibcode: 1989PNAS...86.9183G.
- "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. 1988. doi:10.1073/pnas.85.23.8983. PMID 2848250. Bibcode: 1988PNAS...85.8983K.
- "Association of protein kinase A and protein phosphatase 2B with a common anchoring protein". Science 267 (5194): 108–11. 1995. doi:10.1126/science.7528941. PMID 7528941. Bibcode: 1995Sci...267..108C.
- "X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex". Cell 82 (3): 507–22. 1995. doi:10.1016/0092-8674(95)90439-5. PMID 7543369.
- "Calcineurin functions in Ca(2+)-activated cell death in mammalian cells". J. Cell Biol. 131 (3): 735–43. 1995. doi:10.1083/jcb.131.3.735. PMID 7593193.
- "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. 1993. doi:10.1016/0167-4889(93)90117-8. PMID 8392375. https://zenodo.org/record/1258387.
- "Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux". Cell 83 (3): 463–72. 1995. doi:10.1016/0092-8674(95)90124-8. PMID 8521476.
- "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature 378 (6557): 641–4. 1995. doi:10.1038/378641a0. PMID 8524402. Bibcode: 1995Natur.378..641K.
- "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. 1996. doi:10.1159/000134198. PMID 8978785. https://zenodo.org/record/1235418.
- "Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2". Nature 386 (6626): 728–31. 1997. doi:10.1038/386728a0. PMID 9109491. Bibcode: 1997Natur.386..728S.
- "AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region". J. Biol. Chem. 273 (42): 27412–9. 1998. doi:10.1074/jbc.273.42.27412. PMID 9765270.
- "Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD". Science 284 (5412): 339–43. 1999. doi:10.1126/science.284.5412.339. PMID 10195903. Bibcode: 1999Sci...284..339W.
- "DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways". Hum. Mol. Genet. 9 (11): 1681–90. 2000. doi:10.1093/hmg/9.11.1681. PMID 10861295.
- "DNA cloning using in vitro site-specific recombination". Genome Res. 10 (11): 1788–95. 2000. doi:10.1101/gr.143000. PMID 11076863.
- "Calsarcins, a novel family of sarcomeric calcineurin-binding proteins". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14632–7. 2000. doi:10.1073/pnas.260501097. PMID 11114196. Bibcode: 2000PNAS...9714632F.
- "Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism". Endocrinology 142 (5): 1752–9. 2001. doi:10.1210/endo.142.5.8156. PMID 11316738.
External links
- Calcineurin at the US National Library of Medicine Medical Subject Headings (MeSH)
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