Calcineurin (CaN) is acalcium andcalmodulin dependentserine/threonine protein phosphatase (also known asprotein phosphatase 3, and calcium-dependent serine-threonine phosphatase).^[2] It activates theT cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), atranscription factor, bydephosphorylating it. The activated NFATc is thentranslocated into the nucleus, where it upregulates the expression ofinterleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of theT cell response. Calcineurin is the target of a class of drugs calledcalcineurin inhibitors, which includeciclosporin,voclosporin,pimecrolimus andtacrolimus.

Calcineurin is a highly conserved protein withineukaryotic life, appearing within organisms fromyeasts tomammals.^[3]

Calcineurin is a heterodimer of a 61-kD calmodulin-binding catalytic subunit, calcineurin A and a 19-kD Ca²⁺-binding regulatory subunit, calcineurin B. In humans, there are three isozymes of the catalytic subunit, each encoded by a separate gene (PPP3CA,PPP3CB, andPPP3CC) and two isoforms of the regulatory, also encoded by separate genes (PPP3R1,PPP3R2).

Calcineurin A contains the active site, which is between 57-9 kDa depending on isoform, with larger catalytic subunits found in lower eukaryotes such asSaccharomyces fungus.^[3] This catalytic subunit consists of a catalytic domain homologous to otherserine/threonine protein phosphatases as well as three unique regulatory domains at the COOH terminus.^[3] These three regulatory domains were found to be the binding domain of the regulatory subunit of calcineurin B, the domain forcalmodulin binding, and the autoinhibitory domain.^[3] Whencalmodulin or Ca²⁺ is absent, the autoinhibitory domain binds to the active site, inhibiting activity.^[3] Conformational changes with the binding ofcalmodulin or Ca²⁺ frees the active site and resumes calcineurin function.^[3]

When anantigen-presenting cell interacts with aT cell receptor onT cells, there is an increase in the cytoplasmic level of calcium, which activates calcineurin by binding a regulatory subunit and activatingcalmodulin binding.^[4] 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 ofcytotoxic lymphocytes. 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 theNFAT1 transcription complex, operating through direct binding through a conserved N terminus.^[5] Translocation of theNFAT transcription factors into the nucleus is maintained via the concentration of Ca²⁺ ions due to the integration of Ca²⁺ signaling withinmitogen-activated protein kinase inNFAT, the activity ofCalmodulin can act as a coincidence detector for Ras signaling pathways.^[5] Dissociation of histone deacetylase 4 (HDAC) by calcineurin leads to regulation of theMef2 transcription factor, which mediates transition of fast muscle fibers to slow muscle fibers.^[5] 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 ofprogrammed cell death.^[5]

Calcineurin is suggested to be a critical component in the formation of synaptic connections. NFATc4 is found to be expressed inhippocampal neurons, with translocation viadepolarization and normal synaptic activity.^[5] This in conjunction with a potential downstream gene encoding a Ca²⁺ channel (IP3R1) form the basis for the potential linkage of calcineurin to synaptic connections, especially within newborn animals which have activation of IP3R1.^[5] 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.

Heart valve formation andmyocardial 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,^[5] meaning that the calcineurintranscription factor controls a vital developmental pathway for survival of newborn animals. In transgenic mice presenting this mutation are shown to die fromcongestive heart failure in utero.^[3] 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.^[5] Additionally, overexpression of NFATc4 could also induce similar results, and cyclosporin A prevents cardiac hypertrophy development in response to certain stimuli.^[5]

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.^[5] This is shown through the augmentation of suboptimal stimuli through the use of calcium, as well as blocking by cyclosporin A.^[5]

Mediation of pheromone-induced growth arrest for mating is performed by a Ca²⁺ increase and activation of calcineurin.^[3] Strains lacking in either of two yeast calcineurin A subunits were unable to recover from growth arrest.^[3]Calmodulin is also found to be required from this growth arrest,^[3] 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 inasexual reproduction.

Presence and abundance of Calcineurin Aα in mice affects the intensity ofnon-rapid eye movement sleep (NREMS).^[6] In mice which overexpression of the protein subunit occurs, it is observed that the amount of sleep and as a result wakefulness is increased.^[6] Furthermore, deficiency or knockout of the subunit leads to diminishedNREMS in affected mice,^[6] showing the coupling of sleep with the function of the calcineurin protein. Severeinsomnia was also exhibited in mice which lacked CnB1, as well as an increased circadian period as compared to wild type mice.^[6]

Calcineurin inhibitors are prescribed for adultrheumatoid arthritis (RA) as a single drug or in combination withmethotrexate. 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 ocularBehçet's disease,juvenile idiopathic arthritis, adult and juvenilepolymyositis anddermatomyositis, adult and juvenilesystemic lupus erythematosus, adult lupusmembranous nephritis,systemic sclerosis,aplastic anemia, steroid-resistantnephrotic syndrome,atopic dermatitis, severe corticosteroid-dependentasthma, severeulcerative colitis,pemphigus vulgaris,myasthenia gravis, anddry eye disease, with or withoutSjögren's syndrome (administered as ophthalmic emulsion).^[7]

Calcineurin is linked to receptors for several brain chemicals includingglutamate,dopamine andGABA.^[8] An experiment with genetically-altered mice that could not produce calcineurin showed similar symptoms as in humans withschizophrenia: impairment inworking memory, attention deficits, aberrant social behavior, and several other abnormalities characteristic of schizophrenia.^[9]

Calcineurin along with NFAT, may improve the function of diabetics'pancreaticbeta cells.^[10][11] Thus tacrolimus contributes to the frequent development of new diabetes following renal transplantation.^[12]

Calcineurin/NFAT signaling is required for perinatal lung maturation and function.^[13]

Calcineurin inhibitors such astacrolimus andciclosporin are used to suppress the immune system in organallotransplant recipients to prevent rejection of the transplanted tissue.^[14]

Calcineurin has been shown tointeract withRCAN1^[15] andAKAP5.^[16]

Inhibition of calcineurin is also found to be performed by encoded proteins in viruses. Notably, theAfrican swine fever virus encodes the A238L protein, which binds to calcineurin and inhibits translocation and function of NFATc.^[5] Given sequence similarity between A238L and NFATc family members suggests that the protein induces cyclosporin-likeimmunosuppression in host cells.^[5]

• Calcineurin at the U.S. National Library of MedicineMedical Subject Headings (MeSH)

• Genes on human chromosome 4
• Genes on human chromosome 10
• Genes on human chromosome 8
• Genes on human chromosome 2
• Genes on human chromosome 9
• Signal transduction
• EC 3.1.3

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• Short description matches Wikidata
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