Alternative titles; symbols
HGNC Approved Gene Symbol: PPP3CB
Cytogenetic location: 10q22.2 Genomic coordinates (GRCh38): 10:73,436,433-73,496,024 (from NCBI)
Calcineurin, a calmodulin-regulated protein phosphatase, is found in the cells of all eukaryotes ranging from yeast to mammals. Wang et al. (1996) described this heterodimeric protein as having a 19-kD Ca(2+)-binding regulatory subunit, calcineurin B, and a 58- to 59-kD catalytic subunit, calcineurin A. One gene encodes calcineurin B (PPP3R1; 601302) in all tissues except testis, and it is highly conserved at the level of both protein and DNA sequences in eukaryotes. In contrast, there are 2 major isoforms, alpha (PPP3CA; 114105) and beta (PPP3CB), of calcineurin A encoded by separate genes located on different human chromosomes. A third isoform, A-gamma (PPP3CC; 114107), is unique to testis. Additional diversity of calcineurin A is created by alternative splicing of mRNAs. Calcineurin is especially abundant in brain where it constitutes 1% of total protein.
By Southern analysis of human/hamster hybrid cell lines, Giri et al. (1991) demonstrated that the CALNA2 gene is located on chromosome 10. Wang et al. (1996) confirmed the assignment to chromosome 10 by Southern blot analysis and regionalized the assignment to 10q21-q22 by isotopic in situ hybridization.
Wang et al. (2011) found that Cna-alpha and -beta were critical in executing a proapoptotic program following exposure of neonatal rat cardiomyocytes to anoxia. Cna-alpha and -beta dephosphorylated the mitochondrial fission protein Drp1 (DNM1L; 603850), permitting translocation of Drp1 from the cytosol to mitochondria, followed by mitochondrial fragmentation and apoptosis. Wang et al. (2011) characterized upstream events in this apoptotic pathway and found that p53 (191170) downregulated expression of microRNA-499 (MIR499; 613614), which relieved Mir499-dependent repression of Cna-alpha and -beta. Knockdown of either Cna-alpha or Cna-beta via small interfering RNA attenuated Drp1 accumulation in mitochondria, mitochondria fragmentation, and anoxia-induced cell death.
In cardiomyocytes, calcineurin signaling has been implicated in the regulation of the hypertrophic response caused by pressure overload or neuroendocrine stimulation. Bueno et al. (2002) evaluated the necessary function of calcineurin as a hypertrophic regulatory factor by disrupting 1 of the 3 genes that encode the catalytic subunit, calcineurin A-beta, in the mouse. Calcineurin A-beta-deficient mice were viable, fertile, and overtly normal into adulthood, but displayed an 80% decrease in calcineurin enzymatic activity in the heart that was associated with a 12% reduction in basal heart size. Deficient mice were dramatically impaired in their ability to mount a productive hypertrophic response induced by pressure overload, angiotensin II (300034) infusion, or isoproterenol infusion. Analysis of marker genes associated with the hypertrophic response revealed a partial defect in the molecular program of hypertrophy. Collectively, these data solidified the hypothesis that calcineurin functions as a central regulator of the cardiac hypertrophic growth response in vivo.
Bueno, O. F., Wilkins, B. J., Tymitz, K. M., Glascock, B. J., Kimball, T. F., Lorenz, J. N., Molkentin, J. D. Impaired cardiac hypertrophic response in calcineurin A-beta-deficient mice. Proc. Nat. Acad. Sci. 99: 4586-4591, 2002. [PubMed: 11904392] [Full Text: https://doi.org/10.1073/pnas.072647999]
Giri, P., Higuchi, S., Kincaid, R. L. Chromosomal mapping of the human genes for the calmodulin-dependent protein phosphatase (calcineurin) catalytic subunit. Biochem. Biophys. Res. Commun. 181: 252-258, 1991. [PubMed: 1659808] [Full Text: https://doi.org/10.1016/s0006-291x(05)81410-x]
Wang, J.-X., Jiao, J.-Q., Li, Q., Long, B., Wang, K., Liu, J.-P., Li, Y.-R., Li, P.-F. miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nature Med. 17: 71-78, 2011. [PubMed: 21186368] [Full Text: https://doi.org/10.1038/nm.2282]
Wang, M. G., Yi, H., Guerini, D., Klee, C. B., McBride, O. W. Calcineurin A alpha (PPP3CA), calcineurin A beta (PPP3CB) and calcineurin B (PPP3R1) are located on human chromosomes 4, 10q21-q22 and 2p16-p15 respectively. Cytogenet. Cell Genet. 72: 236-241, 1996. [PubMed: 8978785] [Full Text: https://doi.org/10.1159/000134198]