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).
protein phosphatase 3, catalytic subunit, alpha isozyme
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. 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. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.
Calcineurin inhibitors are prescribed for adult rheumatoid arthritis (RA) as a single drug [1-5], or in combination with methotrexate [6,7]. The microemulsion formulation is approved by the Federal Drug Administration of the United States for treatment of severely active RA. It is also prescribed for: Psoriatic arthritis [8,9], Psoriasis [10-12], Acute ocular Behçet’s disease , Juvenile idiopathic arthritis [14,15], Adult and juvenile polymyositis and dermatomyositis [14-21], Adult and juvenile systemic lupus erythematosus [22-25], Adult lupus membranous nephritis , Systemic sclerosis [27-29], Aplastic anemia [30,31], Steroid-resistant nephrotic syndrome (see "Treatment of minimal change disease in adults" and "Treatment of primary focal segmental glomerulosclerosis"), Atopic dermatitis (see "Epidemiology, clinical manifestations, and diagnosis of atopic dermatitis (eczema)"), Severe, corticosteroid-dependent asthma (see "Alternative and experimental agents for the treatment of asthma"), Severe ulcerative colitis [32-34], Pemphigus vulgaris , Myasthenia gravis , and, Dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion) .
Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA. 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.
Calcineurin along with NFAT, may improve the function of diabetics' pancreaticbeta cells. Thus Tacrolimus contributes to the frequent development of new diabetes following renal transplantation.
Calcineurin/Nfat signaling is required for perinatal lung maturation and function.
^PDB1AUI; Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW (December 1995). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature378 (6557): 641–4. doi:10.1038/378641a0. PMID8524402.
^Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L. (March 2005). "Crystal Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis". Mol Biol Rep32 (1): 41–45. doi:10.1007/s11033-004-4250-4. PMID15865209.
^Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S (July 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. PMID10861295.
^Kashishian A, Howard M, Loh C, Gallatin WM, Hoekstra MF, Lai Y (October 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. PMID9765270.
Cottrell JR, Levenson JM, Kim SH, Gibson HE, Richardson KA, Sivula M, Li B, Ashford CJ, Heindl KA, Babcock RJ, Rose DM, Hempel CM, Wiig KA, Laeng P, Levin ME, Ryan TA, Gerber DJ (July 2013). "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. doi:10.1523/JNEUROSCI.5362-12.2013. PMID23825400.
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. PMID1659808.
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. PMID2162844.
Coghlan VM, Perrino BA, Howard M, et al. (1995). "Association of protein kinase A and protein phosphatase 2B with a common anchoring protein". Science267 (5194): 108–11. doi:10.1126/science.7528941. PMID7528941.
Griffith JP, Kim JL, Kim EE, et al. (1995). "X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex". Cell82 (3): 507–22. doi:10.1016/0092-8674(95)90439-5. PMID7543369.
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. Acta1178 (1): 117–20. doi:10.1016/0167-4889(93)90117-8. PMID8392375.
Cameron AM, Steiner JP, Roskams AJ, et al. (1996). "Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux". Cell83 (3): 463–72. doi:10.1016/0092-8674(95)90124-8. PMID8521476.
Kissinger CR, Parge HE, Knighton DR, et al. (1996). "Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex". Nature378 (6557): 641–4. doi:10.1038/378641a0. PMID8524402.
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. PMID8978785.
Shibasaki F, Kondo E, Akagi T, McKeon F (1997). "Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2". Nature386 (6626): 728–31. doi:10.1038/386728a0. PMID9109491.
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. PMID9765270.
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. PMID10861295.
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". Endocrinology142 (5): 1752–9. doi:10.1210/en.142.5.1752. PMID11316738.