Calcineurin

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Crystallographic structure of calcineurin heterodimer composed of the catalytic (PPP3CA and regulatory (PPP3R1) subunits.[1]

Calcineurin (CN) is a 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 T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which includes cyclosporine, pimecrolimus and tacrolimus.

Structure[edit]

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
Identifiers
Symbol PPP3CA
Alt. symbols CALN, CALNA
Entrez 5530
HUGO 9314
OMIM 114105
RefSeq NM_000944
UniProt Q08209
Other data
Locus Chr. 4 q24
protein phosphatase 3, catalytic subunit, beta isozyme
Identifiers
Symbol PPP3CB
Alt. symbols CALNB
Entrez 5532
HUGO 9315
OMIM 114106
RefSeq NM_021132
UniProt P16298
Other data
Locus Chr. 10 q22.2
protein phosphatase 3, catalytic subunit, gamma isozyme
Identifiers
Symbol PPP3CC
Entrez 5533
HUGO 9316
OMIM 114107
RefSeq NM_005605
UniProt P48454
Other data
Locus Chr. 8 p21.3
protein phosphatase 3, regulatory subunit B, alpha
Identifiers
Symbol PPP3R1
Entrez 5534
HUGO 9317
OMIM 601302
RefSeq NM_000945
UniProt P63098
Other data
Locus Chr. 2 p14
protein phosphatase 3, regulatory subunit B, beta
Identifiers
Symbol PPP3R2
Entrez 5535
HUGO 9318
OMIM 613821
RefSeq NM_147180
UniProt Q96LZ3
Other data
Locus Chr. 9 q31

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[3] 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]

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 [13], 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 [26], 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 [35], Myasthenia gravis [36], and, Dry eye disease, with or without Sjögren's syndrome (administered as ophthalmic emulsion) [37].

Schizophrenia[edit]

Calcineurin is linked to receptors for several brain chemicals including NMDA, dopamine and GABA.[4] 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.[5]

Diabetes[edit]

Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells.[6][7] Thus Tacrolimus contributes to the frequent development of new diabetes following renal transplantation.[8]

Calcineurin/Nfat signaling is required for perinatal lung maturation and function.[9]

Interactions[edit]

Calcineurin has been shown to interact with DSCR1[10] and AKAP5.[11]

References[edit]

  1. ^ 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. doi:10.1038/378641a0. PMID 8524402. 
  2. ^ 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. doi:10.1007/s11033-004-4250-4. PMID 15865209. 
  3. ^ 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. doi:10.1084/jem.191.11.1869. PMC 2213529. PMID 10839803. 
  4. ^ Bannai, H.; Levi, S.; Schweizer, C.; Inoue, T.; Launey, T.; Racine, V.; Sibarita, JB; Mikoshiba, K; Triller, A (2009). "Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics". Neuron 62 (5): 670–682. doi:10.1016/j.neuron.2009.04.023. PMID 19524526. 
  5. ^ 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. doi:10.1073/pnas.1432926100. PMC 166425. PMID 12851457. 
  6. ^ 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. doi:10.1038/nature05097. PMID 16988714. 
  7. ^ Heit JJ (October 2007). "Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics". BioEssays 29 (10): 1011–21. doi:10.1002/bies.20644. PMID 17876792. 
  8. ^ Crutchlow MF, Bloom RD (2007). "Transplant-associated hyperglycemia: a new look at an old problem". Clin J Am Soc Nephrol 2 (2): 343–55. doi:10.2215/CJN.03671106. PMID 17699434. 
  9. ^ 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. doi:10.1172/JCI27331. PMC 1570374. PMID 16998587. 
  10. ^ 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. PMID 10861295. 
  11. ^ 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. PMID 9765270. 

Further reading[edit]

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