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Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase. 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 T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporine, pimecrolimus and tacrolimus.
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).
Mechanism of action Edit
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.
Clinical relevance Edit
Rheumatic diseases Edit
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. 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  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/Nfat signaling is required for perinatal lung maturation and function.
- ↑ PDB 1AUI; 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. Nature 378 (6557): 641–4.
- ↑ 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 Rep 32 (1): 41–45.
- ↑ 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.
- ↑ (2009). Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics. Neuron 62 (5): 670–682.
- ↑ 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.
- ↑ 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.
- ↑ Heit JJ (October 2007). Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics. BioEssays 29 (10): 1011–21.
- ↑ 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.
- ↑ 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.
- ↑ 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.
Further reading Edit
- 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.
- Crabtree GR (1999). Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT. Cell 96 (5): 611–4.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Shibasaki F, McKeon F (1995). Calcineurin functions in Ca(2+)-activated cell death in mammalian cells. J. Cell Biol. 131 (3): 735–43.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Wang HG, Pathan N, Ethell IM, et al. (1999). Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284 (5412): 339–43.
- 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.
- Hartley JL, Temple GF, Brasch MA (2001). DNA Cloning Using In Vitro Site-Specific Recombination. Genome Res. 10 (11): 1788–95.
- 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.
- 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.
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