Alternative titles; symbols
HGNC Approved Gene Symbol: PPP3CC
Cytogenetic location: 8p21.3 Genomic coordinates (GRCh38): 8:22,441,078-22,541,125 (from NCBI)
Calmodulin-dependent protein phosphatase, calcineurin, is involved in a wide range of biologic activities, acting as a Ca(2+)-dependent modifier of phosphorylation status. In testis, the motility of the sperm is thought to be controlled by cAMP-dependent phosphorylation and a unique form of calcineurin appears to be associated with the flagellum. The calcineurin holoenzyme is composed of catalytic and regulatory subunits of 60 and 18 kD, respectively. At least 3 genes, calcineurin A-alpha (CALNA1; 114105), calcineurin A-beta (CALNA2; 114106), and calcineurin A-gamma (CALNA3), have been cloned for the catalytic subunit. These genes have been identified in humans, mice, and rats, and are highly conserved between species (90 to 95% amino acid identity).
Muramatsu and Kincaid (1992) cloned from a human testis library a cDNA for an alternatively spliced variant of the testis-specific catalytic subunit, calcineurin A-gamma. The nucleotide sequence encodes a protein of 502 amino acids. The cDNA sequence differed from the murine form of the gene by a 30-bp deletion in the coding region, the position of which matched those in the 2 other genes for the catalytic subunit. The findings indicated that the alternative splicing event occurred before divergence of the 3 genes. The deduced sequence of the human protein was only 88% identical to the homologous murine form; this indicated a more rapid rate of evolution for the testis-specific gene.
Gerber et al. (2003) noted that calcineurin activity plays a key role in the downstream regulation of dopaminergic signal transduction and in the induction of certain forms of N-methyl-D-aspartate receptor-dependent synaptic plasticity. Thus, calcineurin function could comprise a critical link between dopaminergic and glutamatergic signaling.
By analysis of Southern blots containing DNA from human-hamster somatic cell hybrids, Muramatsu and Kincaid (1992) showed that the CALNA3 gene is located on human chromosome 8. Gerber et al. (2003) stated that the PPP3CC gene maps to chromosome 8p21.3.
Gerber et al. (2003) examined genes encoding calcineurin subunits or calcineurin-related molecules that map to schizophrenia susceptibility loci in the human. Transmission disequilibrium studies in a large sample of affected families suggested association of the PPP3CC gene with schizophrenia. The PPP3CC gene maps within a confirmed schizophrenia susceptibility locus (SCZD6; 603013).
Miyakawa et al. (2003) found that mice with a conditional knockout (KO) of calcineurin exhibited multiple abnormal behaviors related to schizophrenia (181500). They subjected calcineurin-KO mice to a comprehensive behavioral test battery. Mutant mice showed increased locomotor activity, decreased social interaction, and impairments in prepulse inhibition and latent inhibition. In addition, the mutant mice displayed an increased response to the locomotor stimulating effects of MK-801. Collectively, the abnormalities in the mutant mice were considered to be strikingly similar to those described for schizophrenia. The knockout mice in these studies had forebrain-specific knockout.
Miyata et al. (2015) demonstrated that male mice lacking Ppp3cc or Ppp3r2 (613821) genes (knockout mice) are infertile, with reduced sperm motility owing to an inflexible midpiece. Treatment of mice with cyclosporine A or FK506 created phenocopies of the sperm motility and morphologic defects. These defects appeared within 4 to 5 days of treatment, which indicates that sperm-specific calcineurin confers midpiece flexibility during epididymal transit. Male mouse fertility recovered a week after treatment was discontinued. Miyata et al. (2015) suggested that because human spermatozoa contain PPP3CC and PPP3R2 as a form of calcineurin, inhibition of this sperm-specific calcineurin may lead to the development of a reversible male contraceptive that would target spermatozoa in the epididymis.
Gerber, D. J., Hall, D., Miyakawa, T., Demars, S., Gogos, J. A., Karayiorgou, M., Tonegawa, S. Evidence for association of schizophrenia with genetic variation in the 8p21.3 gene, PPP3CC, encoding the calcineurin gamma subunit. Proc. Nat. Acad. Sci. 100: 8993-8998, 2003. [PubMed: 12851458] [Full Text: https://doi.org/10.1073/pnas.1432927100]
Miyakawa, T., Leiter, L. M., Gerber, D. J., Gainetdinov, R. R., Sotnikova, T. D., Zeng, H., Caron, M. G., Tonegawa, S. Conditional calcineurin knockout mice exhibit multiple abnormal behaviors related to schizophrenia. Proc. Nat. Acad. Sci. 100: 8987-8992, 2003. [PubMed: 12851457] [Full Text: https://doi.org/10.1073/pnas.1432926100]
Miyata, H., Satouh, Y., Mashiko, D., Muto, M., Nozawa, K., Shiba, K., Fujihara, Y., Isotani, A., Inaba, K., Ikawa, M. Sperm calcineurin inhibition prevents mouse fertility with implications for male contraceptive. Science 350: 442-445, 2015. [PubMed: 26429887] [Full Text: https://doi.org/10.1126/science.aad0836]
Muramatsu, T., Kincaid, R. L. Molecular cloning and chromosomal mapping of the human gene for the testis-specific catalytic subunit of calmodulin-dependent protein phosphatase (calcineurin A). Biochem. Biophys. Res. Commun. 188: 265-271, 1992. [PubMed: 1339277] [Full Text: https://doi.org/10.1016/0006-291x(92)92379-c]