Department of Pediatric Gastroenterology, Children’s Hospital of Pittsburgh of UPMC,,

Entry Version: 

Version 2.0, September 5, 2014


Muili, Kamaldeen, Orabi, Abrahim and Husain, Sohail. (2014). Calcineurin.
Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2014.8
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Protein symbols: PP2B, Cn

Genes: PPP3CA (CnAα);  PPP3CB, (CnAβ); PPP3CC (CnAγ); PPP3R1 (CnB1); PPP3R2 (CnB2)


Calcineurin (CN) is a Ca2+/calmodulin dependent serine/threonine protein phosphatase first identified in brain and also known as protein phosphatase 2B (PP2B).  It has two subunits, A and B, each of which has several isoforms and is inhibited by the immunosuppressant drugs FK506 and cyclosporine.  A number of endogenous inhibitors have also been identified.  CN has a number of targets but its most prominent are the NFAT (nuclear factor of activated T cells) transcription factors.  In the pancreatic acinar cell CN plays a role in mediating the action of elevated Ca2+ to stimulate cell division, pancreatic growth and protein synthesis.  Pathophysiologically, it is involved in mediating experimental pancreatitis induced by bile salts and caerulein.

1. General Function

Calcineurin (Cn) is a Ca2+/calmodulin (CaM)-dependent serine/threonine phosphatase first identified in extracts of mammalian brain (68, 94). Its name was further derived from its ability to bind Ca2+. Its importance has been documented in a number of physiologic and pathologic conditions including neuronal and muscle development, lymphocyte activation, cardiac hypertrophy, switching of skeletal muscle fiber type, and expression of ion channels. Cn (also known as PP2B) is part of a family of type 2 protein phosphatases that include PP2A and PP2C. They are classified according to their dependence on certain divalent metal ions for phosphatase activity and Cn is uniquely dependent upon Ca2+. PP2A and PP1, but not Cn, are inhibited by the exogenously administered phosphatase inhibitors okadaic acid, microcystin, and calyculin, as well as the endogenous inhibitors inhibitor-1 and DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of 32 kDa). Cn is specifically inhibited by the immunosuppressant drugs FK506 (tacrolimus) and cyclosporine A (CsA) (44).

There are several comprehensive reviews on Cn (4, 68), more recent brief updates (3, 37, 44), information on Cn inhibitors (42, 55), and disease- or organ/tissue-specific reviews relating to Cn in the neurosciences (29), muscle (65), islet cells (35).

Cn isoforms, structure, and function

Cn consists of two subunits, CnA and CnB, which form a heterodimer in order to conduct phosphatase activity. CnA (Figure 1) contains the catalytic domain, which is homologous to other serine/threonine protein phosphatases (4). A dinuclear metal center composed of one iron and one zinc molecule each lies next to a β sandwich on the active site (Figure 2). CnA also has 3 regulatory domains: a binding domain for its partner subunit CnB, a CaM-binding domain, and an autoinhibitory domain. CnB, the regulatory subunit, contains 4 Ca2+-binding EF hand motifs that regulate (through a conformational change) the catalytic function of Cn. CnB binding to CnA may also facilitate proper folding of the active enzyme (21). CnB resembles CaM in that both bind to an extended α helix on their respective CnA domains. The primary sequence of the Cn subunit is highly conserved. CnA and CnB are tightly bound (kd ≤ 10-13 M) even in the total absence of Ca2+. Two short α-helices form the inhibitory domain and block the catalytic center under basal low Ca2+ conditions. The CaM binding domain is flexible. Binding of CaM along with Ca2+ binding to CnB induces displacement of the inhibitory domain, thus exposing the catalytic domain.

Figure 1. Primary sequence and domain structure of CnA. The amino acid sequence represents rat CnAα. Note the regulatory domains that bind CnB and CaM as well as the autoinhibitory domain (AI). Modified from (68).

Figure 2. Cn structure. (left panel) Ribbon diagram of CnA (yellow) and CnB (blue). The former has several disordered regions (DRs) , including a long stretch of 95 residues (red); the CaM binding α helix is contained within the this DR. (right panel) X-ray crystallography of CaM (blue) demonstrates binding to the α helix of CnA (colored yellow). Source:

Cn isoforms and tissue distribution

CnA has 3 isoforms CnAα, CnAβ, and CnAg. CnB has two isoforms CnB1 and CnB2. CnAβ also has two splice variants which differ in their C-terminal domain (30). CnAα and CnAβ appear to interact interchangeably with CnB1. Cn is highly enriched in brain; it constitutes 1% of total protein content and there are 20-30 fold greater amounts than in other tissues. However, Cn is ubiquitously expressed and has differential isoform distribution. CnAg and CnB2 are primarily found in testis. There is greater abundance of CnAα over CnAβ in brain and heart, but the reverse is true in spleen, thymus, and lymphocytes. CnAβ is considered a stress-responsive isoform (12, 84).

The subcellular distribution of Cn is also distinct in certain cell types. Although Cn is localized to the cytoplasm in most systems, in spermatids, for example, it is localized to the nucleus; levels are most abundant during the initial stage of nuclear elongation with almost no signal present in the cytoplasm (57). In some systems, Cn co-translocates with NFAT (nuclear factor of activated T cells) to the nucleus upon activation by Ca2+ (76). In chicken forebrain, Cn is highly enriched in cytoplasmic, microsomal, and synaptosomal fractions (1). Cn is also co-localized with the cytoskeleton in cultured neurons (22) and the T-tubules of ventricular myocytes (70). The molecular mechanism of this targeting is not fully clear. However, calsarcin-1 and -2 tether Cn to α-actinin and may couple Cn activity with muscle contraction (23).

Regulation of Cn

Several factors regulate Cn. The most potent activators are Ca2+ and CaM. As mentioned earlier, even at low cytosolic Ca2+ concentrations, CnA is tightly bound to CnB (49). However, a sustained rise in Ca2+ causes the dual recruitment of CaM to CnA and the binding of Ca2+ to CnB (89). The type of Ca2+ signature necessary for Cn activation is unclear. Using NFAT nuclear translocation as a measure of Cn activation, Timmerman et al. demonstrated in lymphocytes that sustained, but not transient elevations were required to maintain NFAT in the nucleus (89). However, Dolmetsch et al. demonstrated in the same cell type that rapid oscillations in Ca2+ could induce NFAT translocation (19). Nonetheless, the rise in cytosolic Ca2+ results in a conformational change in CnA that forces its autoinhibitory domain to dissociate from its catalytic groove, thereby permitting Cn activity. Of the two initiating components, it is thought that CaM is the critical activator. Cn is also reversibly inactivated by oxidation of its Fe2+ molecule (95). In fact, there is some thought that a Ca2+/CaM-induced conformational change in Cn exposes the Fe2+ to oxidation, thus providing negative feedback for Cn activation.

A number of endogenous Cn inhibitors have been identified. They include AKAP79 (A-kinase anchoring protein of 79 kDa) which as its name implies also anchors PKA with Cn (17). Another protein with this dual anchoring and inhibitory action on Cn in cardiac and skeletal muscle is calsarcin (23). A family of proteins called modulatory Cn interacting proteins (MCIPs) serves as feedback inhibitors of Cn (67). In humans, its gene was initially identified as DSCR1 (Downs’s syndrome critical region 1) (81). A recent consensus was reached to call these proteins regulators of Cn (RCANs) (15). They are upregulated by Cn-mediated activation of the transcription factor NFAT. They can inhibit Cn and interestingly also directly inhibit NFAT through binding a highly conserved ISPPxSPP motif found on both proteins. Other inhibitors include Cn homologous protein (CHP) and Cain/Cabin1 (46). The latter is a 240 kDa nuclear protein that inhibits Cn in a Ca2+- and PKC-dependent manner, likely by binding to the same site as FK506-FKBP. Other factors contributing to Cn activation include polyunsaturated fatty acids (43).

Cn targets

Several phospho-protein targets of Cn have been identified. The best known is NFAT, which resides in the cytoplasm during basal conditions, but translocates to the nucleus upon dephosphorylation by Cn (52). Other targets of Cn are listed in Table 1.

Cn in physiology and disease

As mentioned earlier, Cn is highly enriched in neurons, but it is ubiquitously expressed in all tissues and cells. In the brain, it functions to activate a series of phosphatases by dephosphorylating the endogenous inhibitors of PP-1: inhibitor-1 and DARPP-32. Cn thus intricately regulates synaptic plasticity and long term memory (53, 103). Cn also regulates synaptic vesicle endocytosis by dephosphorylating the dephosphins (14). In T cells, sustained cytosolic Ca2+ release leads to Cn/NFAT activation and the induction of T cell-activating genes, notably interleukin-2 (52). The reason why the Cn inhibitors FK506 and CsA are such effective chronic immunosuppressive drugs is the blockade of T cell Cn. In heart, the Cn/NFAT pathway may protect against dilated cardiomyopathy (34). However, it plays a pathologic role in cardiac hypertrophy (56, 83, 100), through either activation of NFAT3 (along with GATA4), co-activation of NFAT and MEF2, or PKC activation. In skeletal muscle, Cn regulates, again through NFAT3 and MEF2, switching of muscle fiber subtype (65, 102). In islet cells Cn/NFAT regulates beta cell growth (36, 41) and survival (6, 79).

2. Cn in the exocrine pancreas

Investigations in the exocrine pancreas relating to Cn have focused on the acinar cell. Cn was reported to inhibit acinar cell exocytosis of pancreatic enzymes (18, 27, 97). Initial work in both pancreatic lobules as well as dispersed acini demonstrated that CsA and FK506 each reduced caerulein- and carbachol-stimulated amylase secretion (18, 27, 97). However, later studies could reproduce only a modest reduction using FK506 (27, 40). Further work showed that Cn is required for translational control of acinar cell protein synthesis. In isolated acinar cells stimulated with either CCK, bombesin, or carbachol, FK506 reduced methionine incorporation into protein. FK506 modulated factors in the translation machinery: it reduced the phosphorylation of mRNA cap binding protein eukaryotic initiation factor (eIF) 4E binding protein, reduced the formation of the eIF4F complex, and increased the phosphorylation of eukaryotic elongation factor 2 (69). In a series of elegant studies using an experimental model of adaptive growth in which mice were fed the trypsin inhibitor camostat in order to stimulate endogenous CCK release, pancreatic growth was shown to be dependent upon Cn (32, 33, 87). This was initially demonstrated using CsA and FK506 (87). Cn pathways could explain several important aspects of pancreatic growth, such as c-Jun NH2-terminal kinase activation (86). In a subsequent study, overexpression of the endogenous Cn inhibitor Rcan1 selectively within acinar cells also led to reduced adaptive growth of the pancreas (32). Because Rcan1 is a transcriptional target of NFAT, validated in the acinar cell by chromatin immunoprecipitation, it was suggested that Cn modulates growth through NFAT activation (32). Indeed, using an NFAT-luciferase reporter, CCK activated NFAT signaling (33).

Cn has also been shown to mediate experimental pancreatitis (40, 60, 73). FK506 administration in vivo attenuated the severity of pancreatitis induced by intra-ductal bile acid infusion or hyperstimulation with the CCK analog caerulein. Further, the Cn inhibitors FK506, CsA, and Cn inhibitory peptide (CiP) reduced pathologic intra-acinar protease activation, NF-κB activation, and cell injury (58-60). Similarly, NF-κB activation due to thapsigargin-induced Ca2+ signals was dependent on Cn (31). CsA was shown to attenuate pancreatic inflammation in an experimental model of chronic pancreatitis that was induced in the MRL/MP mouse strain by injecting poly IC (polyinosinic:polycytidylic acid) (72). In this model, it was suggested that the effect of Cn in chronic pancreatitis was mediated through auto-activated T cells.

There are also reports that NFAT is involved in pancreatic injury (5). Mice deficient in NFATc3 had reduced trypsinogen activation, pancreatic inflammation, and were protected against intra-ductal bile infusion or L-arginine-induced pancreatitis. Other Cn substrates that mediate non-transcriptional events may also play a role in the exocrine pancreas. Notably, the Cn substrate CRHSP-24 was first identified in the exocrine pancreas (28, 47).

3. Tools for the study of Cn

a. Molecular constructs

Several Cn clones and adenoviral constructs have been created. A major tool employed to identify a role for Cn in a cellular process has been the overexpression of a CaM-independent derivative of CnAα residues (1-392), in effect producing a constitutively active Cn (ΔCnA) (64). A host of plasmids are available for purchase at Addgene ( ). Adenoviral vectors are available from Seven Hills Bioreagents. siRNA for Cn is available through Ambion.

b. Antibodies

In our experience, commercially available Cn antibodies are not particularly specific for their labeled Cn isoforms, particularly the CnAβ antibody. However, they are available from Santa Cruz, Upstate Biotech, BD Transduction Labs, and Chemicon. Most of them can be used for immunofluorescence in addition to western blotting.

c. Transgenic mice

CnAβ knockout mice were made by Dr. Jeff Molkentin (12). They live to adulthood, breed well, and have no gross phenotypic defects. CnAα knockout mice were made Dr. Jon Seidman (104). CnB1 knockout mice do not live beyond the embryonic period due to fatal defects in vascular patterning. However, floxed CnB1 mice were made by Dr. Gerald Crabtree (62). To our knowledge, CnAg-/- or CnB2-/- are not available. An NFAT luciferase reporter mouse has been used to monitor Cn activation (99).

d. Cn Activity

Cn activity is primarily measured in vitro using a 19 residue synthetic peptide corresponding to residues 81-99 of the RII subunit of cAMP-dependent protein kinase (8). As an alternative Biomol Labs carries a colorimetric assay kit. In vivo measurements can be performed by monitoring NFAT nuclear translocation. In pancreas the dephosphorylation of CRHSP-24 has also been used (48). As mentioned earlier, there are adenoviral NFAT-reporter constructs and transgenic NFAT-luciferase mice (99).

e.Pharmacologic inhibitors

The two prototypic Cn inhibitors, FK506 and CsA, form a complex with FK506 binding protein (FKBP12) and cyclophilin, respectively (55). The complex then binds Cn and blocks access of substrates to its catalytic site. The junction between CnB and CnA has been identified by crystallography to be the binding site for FK506 (Figure 3). The two inhibitors are widely used in clinical practice as immunosuppressants after organ transplantation or for the treatment of autoimmune disorders because they diminish Cn-dependent T cell activation. Several novel variations of these inhibitors are in testing (77). FK506 is more specific than CsA. The latter can bind cyclophilin D and thereby inhibit the mitochondrial permeability transition pore (101). It should also be noted that both FK506 and CsA have worrisome side effects with prolonged, chronic use, such as hypertension, neurotoxicity and diabetes (91, 92).

CiP is a short peptide that mimics the auto-inhibitory domain of Cn. A cell permeant form of CiP, made by covalently attaching an arginine tail to the peptide is available through Calbiochem (88). As a negative control, however, it will be important to synthesize a scrambled peptide of equal length that also has an arginine tail.

Phosphatase inhibitors that do not inhibit Cn can be used as negative controls to determine the selectivity of an effect for Cn. In particular, the serine/threonine phosphatases PP1 and PP2A can be inhibited by okadaic acid (IC50 20 nM and 0.2 nM, respectively), calyculin-A (IC50 1 nM for both), and microcystin-LR (IC50 0.1 nM for both) (75). The former two inhibitors have been used in pancreatic acinar cells (71), and none inhibit Cn (PP2B) at the noted concentrations.

Figure 3. Ribbon diagram of truncated Cn complexed with FK506-FKBP12. CnA is shown in red and CnB in purple, with myristic acid covalently linked to the N-terminal glycine shown in pink. Iron and zinc are contained within the active site of CnA (yellow and green spheres, respectively), and the bound phosphate is shown in purple. Four molecules of Ca2+ on their respective CnB binding sites are shown as pink spheres. The FK506 (yellow)-FKBP12 (green) complex blocks entry of Cn substrates to the active site on CnA. (Protein Data Bank code 1TCO(26)). Modified from (45).


  1. Anthony FA, Winkler MA, Edwards HH, and Cheung WY. Quantitative subcellular localization of calmodulin-dependent phosphatase in chick forebrain. J Neurosci 8: 1245-1253, 1988. PMID: 2833579
  2. Antoni FA, Smith SM, Simpson J, Rosie R, Fink G, and Paterson JM. Calcium control of adenylyl cyclase: the calcineurin connection. Adv Second Messenger Phosphoprotein Res 32: 153-172, 1998. PMID: 9421590
  3. Aramburu J, Heitman J, and Crabtree GR. Calcineurin: a central controller of signalling in eukaryotes. EMBO Rep 5: 343-348, 2004. PMID: 15060569
  4. Aramburu J, Rao A, and Klee CB. Calcineurin: from structure to function. Curr Top Cell Regul 36: 237-295, 2000. PMID: 10842755
  5. Awla D, Zetterqvist AV, Abdulla A, Camello C, Berglund LM, Spegel P, Pozo MJ, Camello PJ, Regner S, Gomez MF, and Thorlacius H. NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice. Gastroenterology 2012. PMID: 22841788
  6. Bernal-Mizrachi E, Cras-Meneur C, Ye BR, Johnson JD, and Permutt MA. Transgenic overexpression of active calcineurin in beta-cells results in decreased beta-cell mass and hyperglycemia. PLoS One 5: e11969, 2010. PMID: 20689817
  7. Biswas A, Mukherjee S, Das S, Shields D, Chow CW, and Maitra U. Opposing action of casein kinase 1 and calcineurin in nucleo-cytoplasmic shuttling of mammalian translation initiation factor eIF6. J Biol Chem 286: 3129-3138, 2011. PMID: 21084295
  8. Blumenthal DK, Takio K, Hansen RS, and Krebs EG. Dephosphorylation of cAMP-dependent protein kinase regulatory subunit (type II) by calmodulin-dependent protein phosphatase. Determinants of substrate specificity. J Biol Chem 261: 8140-8145, 1986. PMID: 3013843
  9. Bollo M, Paredes RM, Holstein D, Zheleznova N, Camacho P, and Lechleiter JD. Calcineurin interacts with PERK and dephosphorylates calnexin to relieve ER stress in mammals and frogs. PLoS ONE 5: e11925, 2010. PMID: 20700529
  10. Bolsover SR. Calcium signalling in growth cone migration. Cell Calcium 37: 395-402, 2005. PMID: 15820386
  11. Bousette N, Chugh S, Fong V, Isserlin R, Kim KH, Volchuk A, Backx PH, Liu P, Kislinger T, MacLennan DH, Emili A, and Gramolini AO. Constitutively active calcineurin induces cardiac endoplasmic reticulum stress and protects against apoptosis that is mediated by alpha-crystallin-B. Proc Natl Acad Sci U S A 107: 18481-18486, 2010. PMID: 20937869
  12. Bueno OF, Wilkins BJ, Tymitz KM, Glascock BJ, Kimball TF, Lorenz JN, and Molkentin JD. Impaired cardiac hypertrophic response in Calcineurin Abeta -deficient mice. Proc Natl Acad Sci U S A 99: 4586-4591, 2002. PMID: 11904392
  13. Bultynck G, Vermassen E, Szlufcik K, De Smet P, Fissore RA, Callewaert G, Missiaen L, De Smedt H, and Parys JB. Calcineurin and intracellular Ca2+-release channels: regulation or association? Biochem and Biophys Res Commun 311: 1181-1193, 2003. PMID: 14623304
  14. Cousin MA, Tan TC, and Robinson PJ. Protein phosphorylation is required for endocytosis in nerve terminals: potential role for the dephosphins dynamin I and synaptojanin, but not AP180 or amphiphysin. J Neurochem 76: 105-116, 2001. PMID: 11145983
  15. Davies KJ, Ermak G, Rothermel BA, Pritchard M, Heitman J, Ahnn J, Henrique-Silva F, Crawford D, Canaider S, Strippoli P, Carinci P, Min KT, Fox DS, Cunningham KW, Bassel-Duby R, Olson EN, Zhang Z, Williams RS, Gerber HP, Perez-Riba M, Seo H, Cao X, Klee CB, Redondo JM, Maltais LJ, Bruford EA, Povey S, Molkentin JD, McKeon FD, Duh EJ, Crabtree GR, Cyert MS, de la Luna S, and Estivill X. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin. FASEB J  21: 3023-3028, 2007. PMID: 17595344
  16. Dawson TM, Steiner JP, Dawson VL, Dinerman JL, Uhl GR, and Snyder SH. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci U S A 90: 9808-9812, 1993. PMID: 7694293
  17. Dell'Acqua ML, Dodge KL, Tavalin SJ, and Scott JD. Mapping the protein phosphatase-2B anchoring site on AKAP79. Binding and inhibition of phosphatase activity are mediated by residues 315-360. J Biol Chem 277: 48796-48802, 2002. PMID: 12354762
  18. Doi R, Inoue K, Chowdhury P, Kaji H, and Rayford PL. Structural and functional changes of exocrine pancreas induced by FK506 in rats. Gastroenterology 104: 1153-1164, 1993. PMID: 7681795
  19. Dolmetsch RE, Xu K, and Lewis RS. Calcium oscillations increase the efficiency and specificity of gene expression. Nature 392: 933-936, 1998. PMID: 9582075
  20. Dougherty MK, Ritt DA, Zhou M, Specht SI, Monson DM, Veenstra TD, and Morrison DK. KSR2 is a calcineurin substrate that promotes ERK cascade activation in response to calcium signals. Mol Cell 34: 652-662, 2009. PMID: 19560418
  21. Feng B, and Stemmer PM. Interactions of calcineurin A, calcineurin B, and Ca2+. Biochemistry 38: 12481-12489, 1999. PMID: 10493818
  22. Ferreira A, Kincaid R, and Kosik KS. Calcineurin is associated with the cytoskeleton of cultured neurons and has a role in the acquisition of polarity. Mol Biol Cell 4: 1225-1238, 1993. PMID: 8167406
  23. Frey N, Richardson JA, and Olson EN. Calsarcins, a novel family of sarcomeric calcineurin-binding proteins. Proc Natl Acad Sci U S A 97: 14632-14637, 2000. PMID: 11114196
  24. Garcia E, Stracher A, and Jay D. Calcineurin dephosphorylates the C-terminal region of filamin in an important regulatory site: a possible mechanism for filamin mobilization and cell signaling. Arch Biochem Biophys 446: 140-150, 2006. PMID: 16442073
  25. Goto S, Yamamoto H, Fukunaga K, Iwasa T, Matsukado Y, and Miyamoto E. Dephosphorylation of microtubule-associated protein 2, tau factor, and tubulin by calcineurin. J Neurochem 45: 276-283, 1985. PMID: 2987415
  26. Griffith JP, Kim JL, Kim EE, Sintchak MD, Thomson JA, Fitzgibbon MJ, Fleming MA, Caron PR, Hsiao K, and Navia MA. X-ray structure of calcineurin inhibited by the immunophilin-immunosuppressant FKBP12-FK506 complex. Cell 82: 507-522, 1995. PMID: 7543369
  27. Groblewski GE, Wagner AC, and Williams JA. Cyclosporin A inhibits Ca2+/calmodulin-dependent protein phosphatase and secretion in pancreatic acinar cells. J Biol Chem 269: 15111-15117, 1994. PMID: 7515049
  28. Groblewski GE, Yoshida M, Bragado MJ, Ernst SA, Leykam J, and Williams JA. Purification and characterization of a novel physiological substrate for calcineurin in mammalian cells. J Biol Chem 273: 22738-22744, 1998. PMID: 9712905
  29. Groth RD, Dunbar RL, and Mermelstein PG. Calcineurin regulation of neuronal plasticity. Biochem Biophys Res Commun 311: 1159-1171, 2003. PMID: 14623302
  30. Guerini D, and Klee CB. Cloning of human calcineurin A: evidence for two isozymes and identification of a polyproline structural domain. Proc Natl Acad Sci U S A 86: 9183-9187, 1989. PMID: 2556704
  31. Gukovskaya AS, Hosseini S, Satoh A, Cheng JH, Nam KJ, Gukovsky I, and Pandol SJ. Ethanol differentially regulates NF-kappaB activation in pancreatic acinar cells through calcium and protein kinase C pathways. Am J Physiol Gastrointest Liver Physiol 286: G204-213, 2004. PMID: 12958018
  32. Gurda GT, Crozier SJ, Ji B, Ernst SA, Logsdon CD, Rothermel BA, and Williams JA. Regulator of calcineurin 1 controls growth plasticity of adult pancreas. Gastroenterology 139: 609-619, 619 e601-606, 2010. PMID: 20438729
  33. Gurda GT, Guo L, Lee SH, Molkentin JD, and Williams JA. Cholecystokinin activates pancreatic calcineurin-NFAT signaling in vitro and in vivo. Mol Biol Cell 19: 198-206, 2008. PMID: 17978097
  34. Heineke J, Wollert KC, Osinska H, Sargent MA, York AJ, Robbins J, and Molkentin JD. Calcineurin protects the heart in a murine model of dilated cardiomyopathy. J Mol Cell Cardiol 48: 1080-1087, 2010. PMID: 19854199
  35. Heit JJ. Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics. BioEssays 29: 1011-1021, 2007. PMID: 17876792
  36. Heit JJ, Apelqvist AA, Gu X, Winslow MM, Neilson JR, Crabtree GR, and Kim SK. Calcineurin/NFAT signalling regulates pancreatic [beta]-cell growth and function. Nature 443: 345-349, 2006. PMID: 16988714
  37. Hogan PG, and Li H. Calcineurin. Current Biology 15: R442-R443, 2005. PMID: 15964258
  38. Hsu CC, Thomas C, Chen W, Davis KM, Foos T, Chen JL, Wu E, Floor E, Schloss JV, and Wu JY. Role of synaptic vesicle proton gradient and protein phosphorylation on ATP-mediated activation of membrane-associated brain glutamate decarboxylase. J Biol Chem 274: 24366-24371, 1999. PMID: 10446215
  39. Huang CC, Wang JM, Kikkawa U, Mukai H, Shen MR, Morita I, Chen BK, and Chang WC. Calcineurin-mediated dephosphorylation of c-Jun Ser-243 is required for c-Jun protein stability and cell transformation. Oncogene 27: 2422-2429, 2008. PMID: 17952113
  40. Husain SZ, Grant WM, Gorelick FS, Nathanson MH, and Shah AU. Caerulein-induced intracellular pancreatic zymogen activation is dependent on calcineurin. Am J Physiol Gastrointest Liver Physiol 292: G1594-1599, 2007. PMID: 17332472
  41. Jeremy JH. Calcineurin/NFAT signaling in the beta-cell: From diabetes to new therapeutics. BioEssays 29: 1011-1021, 2007. PMID: 17876792
  42. Kapturczak MMH, Meier-Kriesche HHU, and Kaplan BB. Pharmacology of calcineurin antagonists. Transplantation proceedings 36: 25S-32S, 2004. PMID: 15041303
  43. Kessen U, Schaloske R, Aichem A, and Mutzel R. Ca2+/calmodulin-independent activation of calcineurin from Dictyostelium by unsaturated long chain fatty acids. J Biol Chem 274: 37821-37826, 1999. PMID: 10608845
  44. Klee C, and Yang S. Calcineurin. In: Handbook of Cell SignalingElsevier, 2010, p. 705-710.
  45. Klee CB, Ren H, and Wang X. Regulation of the Calmodulin-stimulated Protein Phosphatase, Calcineurin. J Biol Chem 273: 13367-13370, 1998. PMID: 9593662
  46. Lai MM, Burnett PE, Wolosker H, Blackshaw S, and Snyder SH. Cain, a novel physiologic protein inhibitor of calcineurin. J Biol Chem 273: 18325-18331, 1998. PMID: 9660798
  47. Lakshmikuttyamma A, Selvakumar P, and Sharma RK. Interaction between heat shock protein 70 kDa and calcineurin in cardiovascular systems (Review). Int J Mol Med 17: 419-423, 2006. PMID: 16465387
  48. Lee S, Wishart MJ, and Williams JA. Identification of calcineurin regulated phosphorylation sites on CRHSP-24. Biochem Biophys Res Commun 385: 413-417, 2009. PMID: 19477163
  49. Li J, Jia Z, Zhou W, and Wei Q. Calcineurin regulatory subunit B is a unique calcium sensor that regulates calcineurin in both calcium-dependent and calcium-independent manner. Proteins 77: 612-623, 2009. PMID: 19536897
  50. Liu JP, Sim AT, and Robinson PJ. Calcineurin inhibition of dynamin I GTPase activity coupled to nerve terminal depolarization. Science 265: 970-973, 1994. PMID: 8052858
  51. Liu YC, and Storm DR. Dephosphorylation of neuromodulin by calcineurin. J Biol Chem 264: 12800-12804, 1989. PMID: 2546935
  52. Macian F. NFAT proteins: Key regulators of T-cell development and function. Nature Reviews Immunology 5: 472-484, 2005. PMID: 15928679
  53. Malleret G, Haditsch U, Genoux D, Jones MW, Bliss TV, Vanhoose AM, Weitlauf C, Kandel ER, Winder DG, and Mansuy IM. Inducible and reversible enhancement of learning, memory, and long-term potentiation by genetic inhibition of calcineurin. Cell 104: 675-686, 2001. PMID: 11257222
  54. Manukyan I, Galatioto J, Mascareno E, Bhaduri S, and Siddiqui MA. Cross-talk between calcineurin/NFAT and Jak/STAT signalling induces cardioprotective alphaB-crystallin gene expression in response to hypertrophic stimuli. J Cell Mol Med 14: 1707-1716, 2010. PMID: 19538478
  55. Martínez-Martínez S, and Redondo JM. Inhibitors of the calcineurin/NFAT pathway. Curr Med Chem 11: 997-1007, 2004. PMID: 15078162
  56. Molkentin JD, Lu J-R, Antos CL, Markham B, Richardson J, Robbins J, Grant SR, and Olson EN. A Calcineurin-Dependent Transcriptional Pathway for Cardiac Hypertrophy. Cell 93: 215-228, 1998. PMID: 9568714
  57. Moriya M, Fujinaga K, Yazawa M, and Katagiri C. Immunohistochemical localization of the calcium/calmodulin-dependent protein phosphatase, calcineurin, in the mouse testis: its unique accumulation in spermatid nuclei. Cell Tissue Res 281: 273-281, 1995. PMID: 7648621
  58. Muili KA, Ahmad M, Orabi AI, Mahmood SM, Shah AU, Molkentin JD, and Husain SZ. Pharmacological and genetic inhibition of calcineurin protects against carbachol-induced pathological zymogen activation and acinar cell injury. Am J Physiol Gastrointest Liver Physiol 302: G898-905, 2012. PMID: 22323127
  59. Muili KA, Jin S, Orabi AI, Eisses JF, Javed TA, Le T, Bottino R, Jayaraman T, and Husain SZ. Pancreatic acinar cell NF-kappaB activation due to bile acid exposure is dependent on calcineurin. J Biol Chem 2013. PMID: 23744075
  60. Muili KA, Wang D, Orabi AI, Sarwar S, Luo Y, Javed TA, Eisses JF, Mahmood SM, Jin S, Singh VP, Ananthanaravanan M, Perides G, Williams JA, Molkentin JD, and Husain SZ. Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. J Biol Chem 288: 570-580, 2013. PMID: 23148215
  61. Mulkey RM, Endo S, Shenolikar S, and Malenka RC. Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369: 486-488, 1994. PMID: 7515479
  62. Neilson JR, Winslow MM, Hur EM, and Crabtree GR. Calcineurin B1 is essential for positive but not negative selection during thymocyte development. Immunity 20: 255-266, 2004. PMID: 15030770
  63. Nishi A, Bibb JA, Matsuyama S, Hamada M, Higashi H, Nairn AC, and Greengard P. Regulation of DARPP-32 dephosphorylation at PKA- and Cdk5-sites by NMDA and AMPA receptors: distinct roles of calcineurin and protein phosphatase-2A. Journal of Neurochemistry 81: 832-841, 2002. PMID: 12065642
  64. O'Keefe SSJ, Tamura JJ, Kincaid RRL, Tocci MMJ, and O'Neill EEA. FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357: 692-694, 1992. PMID: 1377361
  65. Olson EN, and Williams RS. Calcineurin signaling and muscle remodeling. Cell 101: 689-692, 2000. PMID: 10892739
  66. Pennanen C, Parra V, Lopez-Crisosto C, Morales PE, Del Campo A, Gutierrez T, Rivera-Mejias P, Kuzmicic J, Chiong M, Zorzano A, Rothermel BA, and Lavandero S. Mitochondrial fission is required for cardiomyocyte hypertrophy mediated by a Ca2+-calcineurin signaling pathway. J Cell Sci 127: 2659-2671, 2014. PMID: 24777478
  67. Rothermel BA, Vega RB, and Williams RS. The role of modulatory calcineurin-interacting proteins in calcineurin signaling. Trends Cardiovasc Med 13: 15-21, 2003. PMID: 12554096
  68. Rusnak F, and Mertz P. Calcineurin: Form and Function. Physiol Rev 80: 1483-1521, 2000. PMID: 11015619
  69. Sans MD, and Williams JA. Calcineurin is required for translational control of protein synthesis in rat pancreatic acini. Am J Physiol Cell Physiol 287: C310-319, 2004. PMID: 15044154
  70. Santana LF, Chase EG, Votaw VS, Nelson MT, and Greven R. Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytes. J Physiol (Lond) 544: 57-69, 2002. PMID: 12356880
  71. Schafer C, Steffen H, Krzykowski KJ, Goke B, and Groblewski GE. CRHSP-24 phosphorylation is regulated by multiple signaling pathways in pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 285: G726-734, 2003. PMID: 12801884
  72. Schwaiger T, van den Brandt C, Fitzner B, Zaatreh S, Kraatz F, Dummer A, Nizze H, Evert M, Broker BM, Brunner-Weinzierl MC, Wartmann T, Salem T, Lerch MM, Jaster R, and Mayerle J. Autoimmune pancreatitis in MRL/Mp mice is a T cell-mediated disease responsive to cyclosporine A and rapamycin treatment. Gut 2013. PMID: 23564336
  73. Shah AU, Sarwar A, Orabi AI, Gautam S, Grant WM, Park AJ, Shah AU, Liu J, Mistry PK, Jain D, and Husain SZ. Protease Activation during in vivo Pancreatitis is Dependent upon Calcineurin Activation. Am J Physiol Gastrointest Liver Physiol 2009. PMID: 19713471
  74. Shaw JL, and Chang KT. Nebula/DSCR1 upregulation delays neurodegeneration and protects against APP-induced axonal transport defects by restoring calcineurin and GSK-3beta signaling. PLoS Genet 9: e1003792, 2013. PMID: 24086147
  75. Sheppeck JE, Gauss C-M, and Chamberlin AR. Inhibition of the ser-thr phosphatases PP1 and PP2A by naturally occurring toxins. Bioorganic & Medicinal Chemistry 5: 1739-1750, 1997. PMID: 9354230
  76. Shibasaki F, Price ER, Milan D, and McKeon F. Role of kinases and the phosphatase calcineurin in the nuclear shuttling of transcription factor NF-AT4. Nature 382: 370-373, 1996. PMID: 8684469
  77. Sieber M, and Baumgrass R. Novel inhibitors of the calcineurin/NFATc hub - alternatives to CsA and FK506? Cell Commun Signal 7: 25, 2009. PMID: 19860902
  78. Slupe AM, Merrill RA, Flippo KH, Lobas MA, Houtman JC, and Strack S. A calcineurin docking motif (LXVP) in dynamin-related protein 1 contributes to mitochondrial fragmentation and ischemic neuronal injury. J Biol Chem 288: 12353-12365, 2013. PMID: 23486469
  79. Soleimanpour SA, Crutchlow MF, Ferrari AM, Raum JC, Groff DN, Rankin MM, Liu C, De Leon DD, Naji A, Kushner JA, and Stoffers DA. Calcineurin signaling regulates human islet {beta}-cell survival. J Biol Chem 285: 40050-40059, 2010. PMID: 20943662
  80. Staal JA, Dickson TC, Chung RS, and Vickers JC. Cyclosporin-A treatment attenuates delayed cytoskeletal alterations and secondary axotomy following mild axonal stretch injury. Dev Neurobiol 67: 1831-1842, 2007. PMID: 17702000
  81. Strippoli P, Lenzi L, Petrini M, Carinci P, and Zannotti M. A new gene family including DSCR1 (Down Syndrome Candidate Region 1) and ZAKI-4: characterization from yeast to human and identification of DSCR1-like 2, a novel human member (DSCR1L2). Genomics 64: 252-263, 2000. PMID: 10756093
  82. Sugimoto T, Stewart S, and Guan KL. The calcium/calmodulin-dependent protein phosphatase calcineurin is the major Elk-1 phosphatase. J Biol Chem 272: 29415-29418, 1997. PMID: 9367995
  83. Sussman MA, Lim HW, Gude N, Taigen T, Olson EN, Robbins J, Colbert MC, Gualberto A, Wieczorek DF, and Molkentin JD. Prevention of Cardiac Hypertrophy in Mice by Calcineurin Inhibition. Science 281: 1690-1693, 1998. PMID: 9733519
  84. Taigen T, De Windt LJ, Lim HW, and Molkentin JD. Targeted inhibition of calcineurin prevents agonist-induced cardiomyocyte hypertrophy. PNAS 97: 1196-1201, 2000. PMID: 10655507
  85. Tanaka T, Takeda M, Niigawa H, Hariguchi S, and Nishimura T. Phosphorylated neurofilament accumulation in neuronal perikarya by cyclosporin A injection in rat brain. Methods Find Exp Clin Pharmacol 15: 77-87, 1993. PMID: 8387621
  86. Tashiro M, Dabrowski A, Guo L, Sans MD, and Williams JA. Calcineurin-dependent and calcineurin-independent signal transduction pathways activated as part of pancreatic growth. Pancreas 32: 314-320, 2006. PMID: 16628088
  87. Tashiro M, Samuelson LC, Liddle RA, and Williams JA. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Am J Physiol Gastrointest Liver Physiol 286: G784-790, 2004. PMID: 14684381
  88. Terada H, Matsushita M, Lu Y-F, Shirai T, Li S-T, Tomizawa K, Moriwaki A, Nishio S, Date I, Ohmoto T, and Matsui H. Inhibition of excitatory neuronal cell death by cell-permeable calcineurin autoinhibitory peptide. Journal of neurochemistry 87: 1145-1151, 2003. PMID: 14622094
  89. Timmerman LA, Clipstone NA, Ho SN, Northrop JP, and Crabtree GR. Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression. Nature 383: 837-840, 1996. PMID: 8893011
  90. Tongers J, Fiedler B, Konig D, Kempf T, Klein G, Heineke J, Kraft T, Gambaryan S, Lohmann SM, Drexler H, and Wollert KC. Heme oxygenase-1 inhibition of MAP kinases, calcineurin/NFAT signaling, and hypertrophy in cardiac myocytes. Cardiovasc Res 63: 545-552, 2004. PMID: 15276480
  91. Tufton N, Ahmad S, Rolfe C, Rajkariar R, Byrne C, and Chowdhury TA. New-onset diabetes after renal transplantation. Diabet Med 2014. PMID: 24975051
  92. van Rossum HH, de Fijter JW, and van Pelt J. Pharmacodynamic monitoring of calcineurin inhibition therapy: principles, performance, and perspectives. Ther Drug Monit 32: 3-10, 2010. PMID: 20009796
  93. Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, and Reed JC. Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284: 339-343, 1999. PMID: 10195903
  94. Wang JH, and Desai R. A brain protein and its effect on the Ca2+-and protein modulator-activated cyclic nucleotide phosphodiesterase. Biochem Biophys Res Commun 72: 926-932, 1976. PMID: 186066
  95. Wang X, Culotta VC, and Klee CB. Superoxide dismutase protects calcineurin from inactivation. Nature 383: 434-437, 1996. PMID: 8837775
  96. Wang Y, Shibasaki F, and Mizuno K. Calcium signal-induced cofilin dephosphorylation is mediated by Slingshot via calcineurin. J Biol Chem 280: 12683-12689, 2005. PMID: 15671020
  97. Waschulewski IH, Hall DV, Kern HF, and Edwardson JM. Effects of the immunosuppressants cyclosporin A and FK 506 on exocytosis in the rat exocrine pancreas in vitro. Br J Pharmacol 108: 892-900, 1993. PMID: 7683567
  98. Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, and Wakita T. Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology 59: 1726-1737, 2014. PMID: 24375637
  99. Wilkins BJ, Dai Y-S, Bueno OF, Parsons SA, Xu J, Plank DM, Jones F, Kimball TR, and Molkentin JD. Calcineurin/NFAT Coupling Participates in Pathological, but not Physiological, Cardiac Hypertrophy. Circ Res 94: 110-118, 2004. PMID: 14656927
  100. Wilkins BJ, and Molkentin JD. Calcium-calcineurin signaling in the regulation of cardiac hypertrophy. Biochemical and Biophysical Research Communications 322: 1178-1191, 2004. PMID: 15336966
  101. Woodfield K, Ruck A, Brdiczka D, and Halestrap AP. Direct demonstration of a specific interaction between cyclophilin-D and the adenine nucleotide translocase confirms their role in the mitochondrial permeability transition. Biochem J 336 ( Pt 2): 287-290, 1998. PMID: 9820802
  102. Wu H, Rothermel B, Kanatous S, Rosenberg P, Naya FJ, Shelton JM, Hutcheson KA, DiMaio JM, Olson EN, Bassel-Duby R, and Williams RS. Activation of MEF2 by muscle activity is mediated through a calcineurin-dependent pathway. Embo J 20: 6414-6423, 2001. PMID: 11707412
  103. Zeng H, Chattarji S, Barbarosie M, Rondi-Reig L, Philpot BD, Miyakawa T, Bear MF, and Tonegawa S. Forebrain-specific calcineurin knockout selectively impairs bidirectional synaptic plasticity and working/episodic-like memory. Cell 107: 617-629, 2001. PMID: 11733061
  104. Zhang BW, Zimmer G, Chen J, Ladd D, Li E, Alt FW, Wiederrecht G, Cryan J, O'Neill EA, Seidman CE, Abbas AK, and Seidman JG. T cell responses in calcineurin A alpha-deficient mice. J Exp Med 183: 413-420, 1996. PMID: 8627154