Calcineurin

File:Protein PPP3CA PDB 1aui.png) and regulatory (PPP3R1) subunits.{{PDB|1AUI}}; {{cite journal | vauthors = Kissinger CR, Parge HE, Knighton DR, Lewis CT, Pelletier LA, Tempczyk A, Kalish VJ, Tucker KD, Showalter RE, Moomaw EW | title = Crystal structures of human calcineurin and the human FKBP12-FK506-calcineurin complex | journal = Nature | volume = 378 | issue = 6557 | pages = 641–4 |date=December 1995 | pmid = 8524402 | doi = 10.1038/378641a0 | bibcode = 1995Natur.378..641K | s2cid = 4337105 }}]]

Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase (also known as protein phosphatase 3, and calcium-dependent serine-threonine phosphatase).{{cite journal | vauthors = Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L | title = Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis | journal = Mol. Biol. Rep. | volume = 32 | issue = 1 | pages = 41–5 | date = March 2005 | pmid = 15865209 | doi = 10.1007/s11033-004-4250-4 | s2cid = 43848098 }} 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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|{{Infobox protein

| Name = protein phosphatase 3, catalytic subunit, alpha isozyme

| caption =

| image =

| width =

| HGNCid = 9314

| Symbol = PPP3CA

| AltSymbols = CALN, CALNA

| EntrezGene = 5530

| OMIM = 114105

| RefSeq = NM_000944

| UniProt = Q08209

| PDB =

| ECnumber = 3.1.3.16

| Chromosome = 4

| Arm = q

| Band = 24

| LocusSupplementaryData =

}}

|{{Infobox protein

| Name = protein phosphatase 3, catalytic subunit, beta isozyme

| caption =

| image =

| width =

| HGNCid = 9315

| Symbol = PPP3CB

| AltSymbols = CALNB

| EntrezGene = 5532

| OMIM = 114106

| RefSeq = NM_021132

| UniProt = P16298

| PDB =

| ECnumber = 3.1.3.16

| Chromosome = 10

| Arm = q

| Band = 22.2

| LocusSupplementaryData =

}}

|{{Infobox protein

| Name = protein phosphatase 3, catalytic subunit, gamma isozyme

| caption =

| image =

| width =

| HGNCid = 9316

| Symbol = PPP3CC

| AltSymbols =

| EntrezGene = 5533

| OMIM = 114107

| RefSeq = NM_005605

| UniProt = P48454

| PDB =

| ECnumber = 3.1.3.16

| Chromosome = 8

| Arm = p

| Band = 21.3

| LocusSupplementaryData =

}}

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|{{Infobox protein

| Name = protein phosphatase 3, regulatory subunit B, alpha

| caption =

| image =

| width =

| HGNCid = 9317

| Symbol = PPP3R1

| AltSymbols =

| EntrezGene = 5534

| OMIM = 601302

| RefSeq = NM_000945

| UniProt = P63098

| PDB =

| ECnumber = 3.1.3.16

| Chromosome = 2

| Arm = p

| Band = 14

| LocusSupplementaryData =

}}

|{{Infobox protein

| Name = protein phosphatase 3, regulatory subunit B, beta

| caption =

| image =

| width =

| HGNCid = 9318

| Symbol = PPP3R2

| AltSymbols =

| EntrezGene = 5535

| OMIM = 613821

| RefSeq = NM_147180

| UniProt = Q96LZ3

| PDB =

| ECnumber = 3.1.3.16

| Chromosome = 9

| Arm = q

| Band = 31

| LocusSupplementaryData =

}}

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.{{cite journal | vauthors = Yamashita M, Katsumata M, Iwashima M, Kimura M, Shimizu C, Kamata T, Shin T, Seki N, Suzuki S, Taniguchi M, Nakayama T | title = T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex | journal = J. Exp. Med. | volume = 191 | issue = 11 | pages = 1869–79 | date = June 2000 | pmid = 10839803 | pmc = 2213529 | doi = 10.1084/jem.191.11.1869 }} 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).{{Cite web|url = http://www.uptodate.com/contents/pharmacology-and-side-effects-of-cyclosporine-and-tacrolimus|title = Pharmacology and side effects of cyclosporine and tacrolimus|date = 2014-04-10|website = UpToDate}}

= Schizophrenia =

Calcineurin is linked to receptors for several brain chemicals including glutamate, dopamine and GABA.{{cite journal | vauthors = Bannai H, Lévi S, Schweizer C, Inoue T, Launey T, Racine V, Sibarita JB, Mikoshiba K, Triller A | title = Activity-dependent tuning of inhibitory neurotransmission based on GABAAR diffusion dynamics | journal = Neuron | volume = 62 | issue = 5 | pages = 670–82 | year = 2009 | pmid = 19524526 | doi = 10.1016/j.neuron.2009.04.023 | s2cid = 18512241 | doi-access = free }} 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.{{cite journal | vauthors = Miyakawa T, Leiter LM, Gerber DJ, Gainetdinov RR, Sotnikova TD, Zeng H, Caron MG, Tonegawa S | title = Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 100 | issue = 15 | pages = 8987–92 | date = July 2003 | pmid = 12851457 | pmc = 166425 | doi = 10.1073/pnas.1432926100 | bibcode = 2003PNAS..100.8987M | doi-access = free }}

= Diabetes =

Calcineurin along with NFAT, may improve the function of diabetics' pancreatic beta cells.{{cite journal | vauthors = Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, Kim SK | title = Calcineurin/NFAT signalling regulates pancreatic beta-cell growth and function | journal = Nature | volume = 443 | issue = 7109 | pages = 345–9 | date = September 2006 | pmid = 16988714 | doi = 10.1038/nature05097 | bibcode = 2006Natur.443..345H | s2cid = 4397036 }}{{cite journal | vauthors = Heit JJ | title = Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics | journal = BioEssays | volume = 29 | issue = 10 | pages = 1011–21 | date = October 2007 | pmid = 17876792 | doi = 10.1002/bies.20644 | s2cid = 21027866 }} Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation.{{cite journal | vauthors = Crutchlow MF, Bloom RD | title = Transplant-associated hyperglycemia: a new look at an old problem | journal = Clin J Am Soc Nephrol | volume = 2 | issue = 2 | pages = 343–55 | year = 2007 | pmid = 17699434 | doi = 10.2215/CJN.03671106 | doi-access = free }}

Calcineurin/NFAT signaling is required for perinatal lung maturation and function.{{cite journal | vauthors = Davé V, Childs T, Xu Y, Ikegami M, Besnard V, Maeda Y, Wert SE, Neilson JR, Crabtree GR, Whitsett JA | title = Calcineurin/Nfat signaling is required for perinatal lung maturation and function | journal = J. Clin. Invest. | volume = 116 | issue = 10 | pages = 2597–609 | date = October 2006 | pmid = 16998587 | pmc = 1570374 | doi = 10.1172/JCI27331 }}

= 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.{{Cite web|url=https://www.nzf.org.nz/nzf_4754|title=Tacrolimus|date=1 March 2019|website=New Zealand Formulary v81}}

Interactions

Calcineurin has been shown to interact with RCAN1{{cite journal | vauthors = Fuentes JJ, Genescà L, Kingsbury TJ, Cunningham KW, Pérez-Riba M, Estivill X, de la Luna S | title = DSCR1, overexpressed in Down syndrome, is an inhibitor of calcineurin-mediated signaling pathways | journal = Hum. Mol. Genet. | volume = 9 | issue = 11 | pages = 1681–90 | date = July 2000 | pmid = 10861295 | doi = 10.1093/hmg/9.11.1681 | doi-access = free }} and AKAP5.{{cite journal | vauthors = Kashishian A, Howard M, Loh C, Gallatin WM, Hoekstra MF, Lai Y | title = AKAP79 inhibits calcineurin through a site distinct from the immunophilin-binding region | journal = J. Biol. Chem. | volume = 273 | issue = 42 | pages = 27412–9 | date = October 1998 | pmid = 9765270 | doi = 10.1074/jbc.273.42.27412 | doi-access = free }}

References

External links

{{MeshName|Calcineurin}}

Category:Signal transduction

Category:EC 3.1.3

Calcineurin

Structure

Mechanism of action

Clinical relevance

= Rheumatic diseases =

= Schizophrenia =

= Diabetes =

= Organ transplantation =

Interactions

References

Further reading

External links