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Gene Review

Ppp3ca  -  protein phosphatase 3, catalytic subunit,...

Mus musculus

Synonyms: 2900074D19Rik, AI841391, AW413465, CAM-PRP catalytic subunit, CN, ...
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Disease relevance of Ppp3ca


High impact information on Ppp3ca

  • CaM-BPs were expressed differentially, with B lymphocytes having four times more of the CN-like protein than T lymphocytes, while in thymocytes, a 65K polypeptide was the major CaM-BP [5].
  • The mechanisms underlying the X-linked thymus-independent (B) lymphocyte functional defect in the CBA/N (CN) mice and their F1 progeny were studied [6].
  • These adaptations occurred despite the fact that CnA* muscles displayed threefold higher calcineurin activity and enhanced dephosphorylation of the calcineurin targets NFATc1, MEF2A, and MEF2D [7].
  • Moreover, when calcineurin signaling is compromised with cyclosporin A, muscles from OV wild-type mice display a lower molecular weight form of CnA, originally detected in failing hearts, whereas CnA* muscles are spared this manifestation [7].
  • Here we show that skeletal muscles overexpressing an activated form of calcineurin (CnA*) exhibit a phenotype indistinguishable from wild-type counterparts under normal weightbearing conditions and respond to OV with a similar doubling in cell size and slow fiber number [7].

Chemical compound and disease context of Ppp3ca

  • Because cyclosporin A (CsA) reverses hypertrophy in CN mice, its effects on the time course of the development of sudden death and cardiac dysfunction were assessed [2].
  • To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01) [3].

Biological context of Ppp3ca

  • Inhibiting CnA with cyclosporin A (CsA) leads to nephron deficit in rat metanephric organ cultures and apoptosis in various renal cell lines [8].
  • Consistent with these findings, human genetics studies in a large sample of affected families detected a significant association of the PPP3CC gene, which encodes the CN gamma catalytic subunit with schizophrenia [9].
  • The cloning and characterization of cDNAs for the catalytic subunit of calcineurin (CN) from murine and human brain libraries were carried out using nonisotopic methods [10].
  • In addition to alterations in development, there is an absence of proliferation and an increase of cell death in the NZ with loss of CnA-alpha [11].
  • In summary, absence of CnA-alpha but not CnA-beta leads to a defect in normal maturation of the NZ and glomeruli, alterations in the cell cycle, and impaired kidney function [11].

Anatomical context of Ppp3ca


Associations of Ppp3ca with chemical compounds

  • CnA is a serine/threonine phosphatase activated by intracellular calcium [8].
  • Ca(2+) and Ca(2+)/calmodulin-dependent protein phosphatase calcineurin (CN) have been known to play crucial roles in immune response and inflammation [12].
  • Using mouse peritoneal macrophages and RAW 264.7 macrophage cells, we demonstrated that LPS mobilized intracellular free Ca(2+) and induced CN phosphatase activity. iNOS expression and NO secretion in response to LPS were suppressed by Ca(2+) antagonists (TMB-8, BAPTA/AM, and nifedipine) and CN inhibitor (cyclosporin A) [12].
  • The coding sequences of these two genes are distinguished by the absence (PP2B alpha 1) or the presence (PP2B alpha 2) of an amino terminus containing polyproline [15].
  • The immunosuppressive drugs cyclosporin A and FK506 profoundly inhibit the calcium-dependent signaling pathway in T lymphocytes by interfering with the activity of the calcium/calmodulin (CaM)-dependent serine/threonine phosphatase, calcineurin (CN) [16].

Regulatory relationships of Ppp3ca


Other interactions of Ppp3ca

  • Overexpression of dominant negative mutant of IKKalpha and -beta demonstrates that only IKKbeta is the target for CN [12].
  • We also found that CN mediates NF-kappaB activation via IkappaB-alpha hyperphosphorylation and degradation [12].
  • In the present study, we therefore crossed CnA* mice with mdx mice to determine the suitability of elevating calcineurin activity in preventing the dystrophic pathology [14].
  • In this context, we previously showed that mice expressing enhanced muscle calcineurin activity (CnA*) displayed elevated levels of utrophin around their sarcolemma [14].
  • In this report, we show that the PGC-1alpha promoter is regulated by both CaMKIV and CnA activity [18].

Analytical, diagnostic and therapeutic context of Ppp3ca

  • In agreement with these results, Northern blots of mammalian brain RNA showed transcripts for both genes, with about two to three times more of the PP2B alpha 1 mRNAs, whereas in chicken and lizard, only PP2B alpha 1 transcripts were detected [15].
  • Southern blot analysis showed unique restriction fragments for both genes in seven mammalian species; however, in organisms from two nonmammalian vertebrates (chicken and lizard), hybridization was observed only for PP2B alpha 1 [15].
  • Finally, immunofluorescence experiments using Mac-1 antibodies showed a reduction in the number of infiltrating immune cells in muscles from mdx/CnA* mice [14].
  • We therefore tested the effect of two different CN inhibitors, cyclosporine A (CsA) and FK506, on mouse pancreatic growth induced by oral administration of the synthetic protease inhibitor camostat, a known stimulator of endogenous CCK release [17].
  • In our present study, extract of Fructus cannabis (EFC) with activation of CN, extracted from Chinese traditional medicine, was used to determine the effects on memory and immunity [19].


  1. Calcineurin activity is regulated both by redox compounds and by mutant familial amyotrophic lateral sclerosis-superoxide dismutase. Ferri, A., Gabbianelli, R., Casciati, A., Paolucci, E., Rotilio, G., Carrì, M.T. J. Neurochem. (2000) [Pubmed]
  2. Time-dependent systolic and diastolic function in mice overexpressing calcineurin. Semeniuk, L.M., Severson, D.L., Kryski, A.J., Swirp, S.L., Molkentin, J.D., Duff, H.J. Am. J. Physiol. Heart Circ. Physiol. (2003) [Pubmed]
  3. Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin. Guo, J., Zhan, S., Somers, J., Westenbroek, R.E., Catterall, W.A., Roach, D.E., Sheldon, R.S., Lees-Miller, J.P., Li, P., Shimoni, Y., Duff, H.J. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  4. Calcineurin differentially regulates maintenance and growth of phenotypically distinct muscles. Mitchell, P.O., Mills, S.T., Pavlath, G.K. Am. J. Physiol., Cell Physiol. (2002) [Pubmed]
  5. Differential expression of calmodulin-binding proteins in B, T lymphocytes and thymocytes. Kincaid, R.L., Takayama, H., Billingsley, M.L., Sitkovsky, M.V. Nature (1987) [Pubmed]
  6. X-linked B-lymphocyte immune defect in CBA/N mice. II. Studies of the mechanisms underlying the immune defect. Scher, I., Steinberg, A.D., Berning, A.K., Paul, W.E. J. Exp. Med. (1975) [Pubmed]
  7. Matching of calcineurin activity to upstream effectors is critical for skeletal muscle fiber growth. Dunn, S.E., Chin, E.R., Michel, R.N. J. Cell Biol. (2000) [Pubmed]
  8. Ectopic expression of the homeobox gene Cux-1 rescues calcineurin inhibition in mouse embryonic kidney cultures. Alcalay, N.I., Brantley, J.G., Sharma, M., Gooch, J.L., Vanden Heuvel, G.B. Dev. Dyn. (2007) [Pubmed]
  9. Investigating Gene-to-Behavior Pathways in Psychiatric Disorders: The Use of a Comprehensive Behavioral Test Battery on Genetically Engineered Mice. Takao, K., Miyakawa, T. Ann. N. Y. Acad. Sci. (2006) [Pubmed]
  10. Cloning and characterization of molecular isoforms of the catalytic subunit of calcineurin using nonisotopic methods. Kincaid, R.L., Giri, P.R., Higuchi, S., Tamura, J., Dixon, S.C., Marietta, C.A., Amorese, D.A., Martin, B.M. J. Biol. Chem. (1990) [Pubmed]
  11. Calcineurin A-alpha but not A-beta is required for normal kidney development and function. Gooch, J.L., Toro, J.J., Guler, R.L., Barnes, J.L. Am. J. Pathol. (2004) [Pubmed]
  12. Ca2+/calmodulin-dependent protein phosphatase calcineurin mediates the expression of iNOS through IKK and NF-kappaB activity in LPS-stimulated mouse peritoneal macrophages and RAW 264.7 cells. Kim, Y., Moon, J.S., Lee, K.S., Park, S.Y., Cheong, J., Kang, H.S., Lee, H.Y., Kim, H.D. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  13. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Miyakawa, T., Leiter, L.M., Gerber, D.J., Gainetdinov, R.R., Sotnikova, T.D., Zeng, H., Caron, M.G., Tonegawa, S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  14. Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice. Chakkalakal, J.V., Harrison, M.A., Carbonetto, S., Chin, E., Michel, R.N., Jasmin, B.J. Hum. Mol. Genet. (2004) [Pubmed]
  15. Molecular and phylogenetic analysis of calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit genes. Giri, P.R., Marietta, C.A., Higuchi, S., Kincaid, R.L. DNA Cell Biol. (1992) [Pubmed]
  16. Synergism between the calmodulin-binding and autoinhibitory domains on calcineurin is essential for the induction of their phosphatase activity. Tokoyoda, K., Takemoto, Y., Nakayama, T., Arai, T., Kubo, M. J. Biol. Chem. (2000) [Pubmed]
  17. Calcineurin mediates pancreatic growth in protease inhibitor-treated mice. Tashiro, M., Samuelson, L.C., Liddle, R.A., Williams, J.A. Am. J. Physiol. Gastrointest. Liver Physiol. (2004) [Pubmed]
  18. An autoregulatory loop controls peroxisome proliferator-activated receptor gamma coactivator 1alpha expression in muscle. Handschin, C., Rhee, J., Lin, J., Tarr, P.T., Spiegelman, B.M. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  19. The effect of calcineurin activator, extracted from Chinese herbal medicine, on memory and immunity in mice. Luo, J., Yin, J.H., Wei, Q. Pharmacol. Biochem. Behav. (2003) [Pubmed]
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