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Calcineurin

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

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).

protein phosphatase 3, catalytic subunit, alpha isozyme
Identifiers
SymbolPPP3CA
Alt. symbolsCALN, CALNA
NCBI gene5530
HGNC9314
OMIM114105
RefSeqNM_000944
UniProtQ08209
Other data
EC number3.1.3.16
LocusChr. 4 q24
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StructuresSwiss-model
DomainsInterPro
protein phosphatase 3, catalytic subunit, beta isozyme
Identifiers
SymbolPPP3CB
Alt. symbolsCALNB
NCBI gene5532
HGNC9315
OMIM114106
RefSeqNM_021132
UniProtP16298
Other data
EC number3.1.3.16
LocusChr. 10 q22.2
Search for
StructuresSwiss-model
DomainsInterPro
protein phosphatase 3, catalytic subunit, gamma isozyme
Identifiers
SymbolPPP3CC
NCBI gene5533
HGNC9316
OMIM114107
RefSeqNM_005605
UniProtP48454
Other data
EC number3.1.3.16
LocusChr. 8 p21.3
Search for
StructuresSwiss-model
DomainsInterPro
protein phosphatase 3, regulatory subunit B, alpha
Identifiers
SymbolPPP3R1
NCBI gene5534
HGNC9317
OMIM601302
RefSeqNM_000945
UniProtP63098
Other data
EC number3.1.3.16
LocusChr. 2 p14
Search for
StructuresSwiss-model
DomainsInterPro
protein phosphatase 3, regulatory subunit B, beta
Identifiers
SymbolPPP3R2
NCBI gene5535
HGNC9318
OMIM613821
RefSeqNM_147180
UniProtQ96LZ3
Other data
EC number3.1.3.16
LocusChr. 9 q31
Search for
StructuresSwiss-model
DomainsInterPro

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 and ciclosporin 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

  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. Bibcode:1995Natur.378..641K. doi:10.1038/378641a0. PMID 8524402. S2CID 4337105.
  2. ^ Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L (March 2005). "Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis". Mol. Biol. Rep. 32 (1): 41–5. doi:10.1007/s11033-004-4250-4. PMID 15865209. S2CID 43848098.
  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. ^ "Pharmacology and side effects of cyclosporine and tacrolimus". UpToDate. 2014-04-10.
  5. ^ Bannai H, Lévi 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): 670–82. doi:10.1016/j.neuron.2009.04.023. PMID 19524526. S2CID 18512241.
  6. ^ 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. Bibcode:2003PNAS..100.8987M. doi:10.1073/pnas.1432926100. PMC 166425. PMID 12851457.
  7. ^ 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. Bibcode:2006Natur.443..345H. doi:10.1038/nature05097. PMID 16988714. S2CID 4397036.
  8. ^ 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. S2CID 21027866.
  9. ^ 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.
  10. ^ 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.
  11. ^ "Tacrolimus". New Zealand Formulary v81. 1 March 2019.
  12. ^ 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.
  13. ^ 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.

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