View source for Calcineurin

{{Short description|Class of enzymes}}
[[File:Protein PPP3CA PDB 1aui.png|thumb|Crystallographic structure of calcineurin heterodimer composed of the catalytic ([[PPP3CA]]) and regulatory ([[PPP3R1]]) subunits.<ref name="pmid8524402">{{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 }}</ref>]]

'''Calcineurin''' ('''CaN''') is a [[calcium]] and [[calmodulin]] dependent [[serine/threonine protein phosphatase]] (also known as [[protein]] phosphatase 3, and calcium-dependent serine-threonine phosphatase).<ref name="pmid15865209">{{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 }}</ref> It activates the [[T cells]] of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic ([[NFATC1|NFATc]]), a [[transcription factor]], by [[dephosphorylation|dephosphorylating]] it. The activated NFATc is then [[Protein targeting#Post-translational translocation|translocated]] into the nucleus, where it upregulates the expression of [[interleukin 2]] (IL-2), which, in turn, stimulates the growth and differentiation of the [[Cell immunity|T cell response]]. Calcineurin is the target of a class of drugs called [[Immunosuppressive drug#Drugs acting on immunophilins|calcineurin inhibitors]], which include [[ciclosporin]], [[voclosporin]], [[pimecrolimus]] and [[tacrolimus]].

Calcineurin is a highly conserved protein within [[Eukaryote|eukaryotic]] life, appearing within organisms from [[yeast]]s to [[mammal]]s.<ref name=":0">{{Cite journal |last1=Rusnak |first1=Frank |last2=Mertz |first2=Pamela |date=2000-01-10 |title=Calcineurin: Form and Function |url=https://www.physiology.org/doi/10.1152/physrev.2000.80.4.1483 |journal=Physiological Reviews |language=en |volume=80 |issue=4 |pages=1483–1521 |doi=10.1152/physrev.2000.80.4.1483 |pmid=11015619 |issn=0031-9333|url-access=subscription }}</ref>

== Structure ==
Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca<sup>2+</sup>-binding regulatory subunit, calcineurin B.  In humans, 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]]).

{|
|- valign="top"
|{{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 = 
}}
|}

{|
|- valign="top"
|{{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 = 
}}
|}
Calcineurin A contains the active site, which is between 57-9 kDa depending on isoform, with larger catalytic subunits found in lower eukaryotes such as [[Saccharomyces]] fungus.<ref name=":0" /> This catalytic subunit consists of a catalytic domain homologous to other [[Protein serine/threonine phosphatase|serine/threonine protein phosphatases]] as well as three unique regulatory domains at the COOH terminus.<ref name=":0" /> These three regulatory domains were found to be the binding domain of the regulatory subunit of calcineurin B, the domain for [[calmodulin]] binding, and the autoinhibitory domain.<ref name=":0" /> When [[calmodulin]] or Ca<sup>2+</sup> is absent, the autoinhibitory domain binds to the active site, inhibiting activity.<ref name=":0" /> Conformational changes with the binding of [[calmodulin]] or Ca<sup>2+</sup> frees the active site and resumes calcineurin function.<ref name=":0" />

== Mechanism of action ==

When an [[antigen-presenting cell]] interacts with a [[T cell receptor]] on [[T cell]]s, there is an increase in the cytoplasmic level of calcium, which activates calcineurin by binding a regulatory subunit and activating [[calmodulin]] binding.<ref name="pmid10839803">{{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 }}</ref> Calcineurin induces transcription factors ([[NFAT]]s) 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 T cell|cytotoxic lymphocyte]]s. The amount of IL-2 being produced by the T-helper cells is believed to influence the extent of the immune response significantly.

Calcineurin directly dephosphorylates cytoplasmic subunits of the [[NFATC1|NFAT1]] transcription complex, operating through direct binding through a conserved N terminus.<ref name=":1">{{Cite journal |last=Crabtree |first=Gerald R. |date=January 2001 |title=Calcium, Calcineurin, and the Control of Transcription |journal=Journal of Biological Chemistry |language=en |volume=276 |issue=4 |pages=2313–2316 |doi=10.1074/jbc.R000024200 |pmid=11096121 |doi-access=free }}</ref> Translocation of the [[NFAT]] transcription factors into the nucleus is maintained via the concentration of Ca<sup>2+</sup> ions due to the integration of Ca<sup>2+</sup> signaling within [[mitogen-activated protein kinase]] in [[NFAT]], the activity of [[Calmodulin]] can act as a coincidence detector for Ras signaling pathways.<ref name=":1" /> Dissociation of histone deacetylase 4 ([[Histone deacetylase|HDAC]]) by calcineurin leads to regulation of the [[Mef2]] transcription factor, which mediates transition of fast muscle fibers to slow muscle fibers.<ref name=":1" /> This ability to regulate muscular fiber conversion has implications for the developmental impact of the protein and also is believed to be connected to regulation of [[programmed cell death]].<ref name=":1" />

== Function ==

=== Formation of Structures in Newborn Mammals ===

==== Synaptic Connection ====
Calcineurin is suggested to be a critical component in the formation of synaptic connections. NFATc4 is found to be expressed in [[Hippocampus|hippocampal]] neurons, with translocation via [[depolarization]] and normal synaptic activity.<ref name=":1" /> This in conjunction with a potential downstream gene encoding a Ca<sup>2+</sup> channel (IP3R1) form the basis for the potential linkage of calcineurin to synaptic connections, especially within newborn animals which have activation of IP3R1.<ref name=":1" /> Should further research support the possible connection between this protein and synapse connection, it would open new directions of study for neurological development in animals.

==== Cardiovascular ====
Heart valve formation and [[myocardial hypertrophy]] are also believed to be signaled through the calcineurin signaling pathway. Mutations in the NFATc1 gene are reported to cause failure of development in heart valves,<ref name=":1" /> meaning that the calcineurin [[transcription factor]] controls a vital developmental pathway for survival of newborn animals. In transgenic mice presenting this mutation are shown to die from [[congestive heart failure]] in utero.<ref name=":0" /> Stress-induced hypertrophy, a response in cardiac muscle cells, is dependent on calcium, and was discovered to also be induced by overexpression of calcineurin A.<ref name=":1" /> Additionally, overexpression of NFATc4 could also induce similar results, and cyclosporin A prevents cardiac hypertrophy development in response to certain stimuli.<ref name=":1" />

Calcineurin is also found to play a critical role in the development of several other structures and functions, such as the liver, skin, inflammatory and immune response.<ref name=":1" /> This is shown through the augmentation of suboptimal stimuli through the use of calcium, as well as blocking by cyclosporin A.<ref name=":1" />

=== Cell Cycle Arrest Recovery in [[Saccharomyces cerevisiae]] ===
Mediation of pheromone-induced growth arrest for mating is performed by a Ca<sup>2+</sup> increase and activation of calcineurin.<ref name=":0" /> Strains lacking in either of two yeast calcineurin A subunits were unable to recover from growth arrest.<ref name=":0" /> [[Calmodulin]] is also found to be required from this growth arrest,<ref name=":0" /> meaning that all factors which govern calcineurin activation as well as the protein itself are necessary for proper function of yeast cells. Without the ability to escape growth arrest, yeast cells are unable to exit G1, removing the ability to continue through the cell cycle and engage in [[asexual reproduction]].

=== Functions in Sleep ===
Presence and abundance of Calcineurin Aα in mice affects the intensity of [[non-rapid eye movement sleep]] ([[Non-rapid eye movement sleep|NREMS]]).<ref name=":2">{{Cite journal |last1=Yin |first1=Xin |last2=Zhang |first2=Zihan |last3=Zhou |first3=Rui |last4=Zuo |first4=Peng |last5=Sang |first5=Di |last6=Zhou |first6=Shuang |last7=Shi |first7=Bihan |last8=Chen |first8=Lin |last9=Wu |first9=Chongyang |last10=Guo |first10=Ying |last11=Wang |first11=Fengchao |last12=Zhang |first12=Eric Erquan |last13=Li |first13=Qi |last14=Yanagisawa |first14=Masashi |last15=Liu |first15=Qinghua |date=2025-01-28 |title=Calcineurin governs baseline and homeostatic regulations of non–rapid eye movement sleep in mice |journal=Proceedings of the National Academy of Sciences |language=en |volume=122 |issue=4 |article-number=e2418317122 |doi=10.1073/pnas.2418317122 |pmid=39847332 |pmc=11789068 |issn=0027-8424}}</ref> In mice which overexpression of the protein subunit occurs, it is observed that the amount of sleep and as a result wakefulness is increased.<ref name=":2" /> Furthermore, deficiency or knockout of the subunit leads to diminished [[Non-rapid eye movement sleep|NREMS]] in affected mice,<ref name=":2" /> showing the coupling of sleep with the function of the calcineurin protein. Severe [[insomnia]] was also exhibited in mice which lacked CnB1, as well as an increased circadian period as compared to wild type mice.<ref name=":2" />

== 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 glomerulonephritis|membranous nephritis]], [[Systemic scleroderma|systemic sclerosis]], [[aplastic anemia]], steroid-resistant [[nephrotic syndrome]], [[atopic dermatitis]], severe corticosteroid-dependent [[asthma]], severe [[ulcerative colitis]], [[pemphigus vulgaris]], [[myasthenia gravis]], and [[Dry eye syndrome|dry eye disease]], with or without [[Sjögren's syndrome]] (administered as ophthalmic emulsion).<ref>{{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}}</ref>

=== Schizophrenia ===

Calcineurin is linked to receptors for several brain chemicals including [[glutamate]], [[dopamine]] and [[GABA]].<ref>{{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 }}</ref> 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.<ref name="pmid12851457">{{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 }}</ref>

=== Diabetes ===

Calcineurin along with NFAT, may improve the function of diabetics' [[pancreas|pancreatic]] [[beta cells]].<ref name="pmid16988714">{{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 }}</ref><ref name="pmid17876792">{{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 }}</ref> Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation.<ref name="pmid17699434">{{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 }}</ref>

Calcineurin/NFAT signaling is required for perinatal lung maturation and function.<ref name="pmid16998587">{{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 }}</ref>

=== Organ transplantation ===
Calcineurin inhibitors such as [[tacrolimus]] and [[ciclosporin]] are used to suppress the immune system in organ [[Allotransplantation|allotransplant]] recipients to prevent rejection of the transplanted tissue.<ref>{{Cite web|url=https://www.nzf.org.nz/nzf_4754|title=Tacrolimus|date=1 March 2019|website=New Zealand Formulary v81}}</ref>

== Interactions ==

Calcineurin has been shown to [[Protein-protein interaction|interact]] with [[RCAN1]]<!-- DSCR1 is a former symbol --><ref name="pmid10861295">{{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 }}</ref> and [[AKAP5]].<ref name="pmid9765270">{{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 }}</ref>

== Viral Inhibition ==
Inhibition of calcineurin is also found to be performed by encoded proteins in viruses. Notably, the [[African swine fever virus]] encodes the A238L protein, which binds to calcineurin and inhibits translocation and function of NFATc.<ref name=":1" /> Given sequence similarity between A238L and NFATc family members suggests that the protein induces cyclosporin-like [[immunosuppression]] in host cells.<ref name=":1" />

== References ==
{{Reflist|35em}}

== Further reading ==
{{Refbegin|35em}}
* {{cite journal | vauthors = 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 | title = 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 | journal = J. Neurosci. | volume = 33 | issue = 27 | pages = 10938–49  | date = July 2013 | pmid = 23825400 | doi = 10.1523/JNEUROSCI.5362-12.2013 | pmc=3718364}}
* {{cite journal | vauthors = Crabtree GR | title = Generic signals and specific outcomes: signaling through Ca2+, calcineurin, and NF-AT | journal = Cell | volume = 96 | issue = 5 | pages = 611–4 | year = 1999 | pmid = 10089876 | doi = 10.1016/S0092-8674(00)80571-1 | s2cid = 8817053 | doi-access = free }}
* {{cite journal | vauthors = Giri PR, Higuchi S, Kincaid RL | title = Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit | journal = Biochem. Biophys. Res. Commun. | volume = 181 | issue = 1 | pages = 252–8 | year = 1991 | pmid = 1659808 | doi = 10.1016/S0006-291X(05)81410-X | bibcode = 1991BBRC..181..252R }}
* {{cite journal | vauthors = Kincaid RL, Giri PR, Higuchi S, Tamura J, Dixon SC, Marietta CA, Amorese DA, Martin BM | title = Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods | journal = J. Biol. Chem. | volume = 265 | issue = 19 | pages = 11312–9 | year = 1990 | doi = 10.1016/S0021-9258(19)38593-X | pmid = 2162844 | doi-access = free }}
* {{cite journal | vauthors = Guerini D, Klee CB | title = Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 86 | issue = 23 | pages = 9183–7 | year = 1989 | pmid = 2556704 | pmc = 298458 | doi = 10.1073/pnas.86.23.9183 | bibcode = 1989PNAS...86.9183G | doi-access = free }}
* {{cite journal | vauthors = Kincaid RL, Nightingale MS, Martin BM | title = Characterization of a cDNA clone encoding the calmodulin-binding domain of mouse brain calcineurin | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 85 | issue = 23 | pages = 8983–7 | year = 1988 | pmid = 2848250 | pmc = 282646 | doi = 10.1073/pnas.85.23.8983 | bibcode = 1988PNAS...85.8983K | doi-access = free }}
* {{cite journal | vauthors = Coghlan VM, Perrino BA, Howard M, Langeberg LK, Hicks JB, Gallatin WM, Scott JD | title = Association of protein kinase A and protein phosphatase 2B with a common anchoring protein | journal = Science | volume = 267 | issue = 5194 | pages = 108–11 | year = 1995 | pmid = 7528941 | doi = 10.1126/science.7528941 | bibcode = 1995Sci...267..108C }}
* {{cite journal | vauthors = Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, Navia MA | title = X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex | journal = Cell | volume = 82 | issue = 3 | pages = 507–22 | year = 1995 | pmid = 7543369 | doi = 10.1016/0092-8674(95)90439-5 | s2cid = 15502270 | doi-access = free }}
* {{cite journal | vauthors = Shibasaki F, McKeon F | title = Calcineurin functions in Ca(2+)-activated cell death in mammalian cells | journal = J. Cell Biol. | volume = 131 | issue = 3 | pages = 735–43 | year = 1995 | pmid = 7593193 | pmc = 2120616 | doi = 10.1083/jcb.131.3.735 }}
* {{cite journal | vauthors = Muramatsu T, Kincaid RL | title = Molecular cloning of a full-length cDNA encoding the catalytic subunit of human calmodulin-dependent protein phosphatase (calcineurin A alpha) | journal = Biochim. Biophys. Acta | volume = 1178 | issue = 1 | pages = 117–20 | year = 1993 | pmid = 8392375 | doi = 10.1016/0167-4889(93)90117-8 | url = https://zenodo.org/record/1258387 }}
* {{cite journal | vauthors = Cameron AM, Steiner JP, Roskams AJ, Ali SM, Ronnett GV, Snyder SH | title = Calcineurin associated with the inositol 1,4,5-trisphosphate receptor-FKBP12 complex modulates Ca2+ flux | journal = Cell | volume = 83 | issue = 3 | pages = 463–72 | year = 1995 | pmid = 8521476 | doi = 10.1016/0092-8674(95)90124-8 | s2cid = 11594556 | doi-access = free }}
* {{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 | year = 1995 | pmid = 8524402 | doi = 10.1038/378641a0 | bibcode = 1995Natur.378..641K | s2cid = 4337105 }}
* {{cite journal | vauthors = Wang MG, Yi H, Guerini D, Klee CB, McBride OW | title = Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21-->q22 and 2p16-->p15 respectively | journal = Cytogenet. Cell Genet. | volume = 72 | issue = 2–3 | pages = 236–41 | year = 1996 | pmid = 8978785 | doi = 10.1159/000134198 | url = https://zenodo.org/record/1235418 }}
* {{cite journal | vauthors = Shibasaki F, Kondo E, Akagi T, McKeon F | title = Suppression of signalling through transcription factor NF-AT by interactions between calcineurin and Bcl-2 | journal = Nature | volume = 386 | issue = 6626 | pages = 728–31 | year = 1997 | pmid = 9109491 | doi = 10.1038/386728a0 | bibcode = 1997Natur.386..728S | s2cid = 4277216 }}
* {{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 | year = 1998 | pmid = 9765270 | doi = 10.1074/jbc.273.42.27412 | doi-access = free }}
* {{cite journal | vauthors = Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, Reed JC | title = Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD | journal = Science | volume = 284 | issue = 5412 | pages = 339–43 | year = 1999 | pmid = 10195903 | doi = 10.1126/science.284.5412.339 | bibcode = 1999Sci...284..339W }}
* {{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 | year = 2000 | pmid = 10861295 | doi = 10.1093/hmg/9.11.1681 | doi-access = free }}
* {{cite journal | vauthors = Hartley JL, Temple GF, Brasch MA | title = DNA cloning using in vitro site-specific recombination | journal = Genome Res. | volume = 10 | issue = 11 | pages = 1788–95 | year = 2000 | pmid = 11076863 | pmc = 310948 | doi = 10.1101/gr.143000 }}
* {{cite journal | vauthors = Frey N, Richardson JA, Olson EN | title = Calsarcins, a novel family of sarcomeric calcineurin-binding proteins | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 97 | issue = 26 | pages = 14632–7 | year = 2000 | pmid = 11114196 | pmc = 18970 | doi = 10.1073/pnas.260501097 | bibcode = 2000PNAS...9714632F | doi-access = free }}
* {{cite journal | vauthors = Siddiq A, Miyazaki T, Takagishi Y, Kanou Y, Hayasaka S, Inouye M, Seo H, Murata Y | title = Expression of ZAKI-4 messenger ribonucleic acid in the brain during rat development and the effect of hypothyroidism | journal = Endocrinology | volume = 142 | issue = 5 | pages = 1752–9 | year = 2001 | pmid = 11316738 | doi = 10.1210/endo.142.5.8156 | doi-access = free }}
{{Refend}}

== External links ==
* {{MeshName|Calcineurin}}

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[[Category:Signal transduction]]
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