Science. 350(6259):442-445 2015/10/23

Calcineurin is a calcium-dependent phosphatase that is expressed ubiquitously. Cyclosporine A (CsA) and FK506 are calcineurin inhibitors that are widely used as immunosuppressant drugs after solid organ transplantation. In toxicity tests using rats and mice, it has been reported that these drugs also impair male fertility. However, the mechanism of its action was unclear. We identified PPP3CC and PPP3R2 as an isoform of calcineurin (sperm calcineurin) that is localized specifically in the spermatozoa. When we generated genetically modified mice that lack sperm calcineurin, we found that the male mice were sterile because the part of the sperm tail (the midpiece) was inflexible. When we treated the wild-type male mice with CsA or FK506, their midpieces also became inflexible after several days of treatment and the male mice became sterile after 2 weeks. Spermatozoa are made in the testis and transit through the epididymis in about 10 days and spermatozoa gain motility during this transit. Because the sperm midpiece became inflexible due to CsA or FK506 treatment within 10days, these results indicated that sperm calcineurin confers midpiece flexibility during sperm maturation in the epididymis but not during spermatogenesis in the testis. Since male fertility recovered 1 week after discontinuation of the drugs, specific inhibition of sperm calcineurin may lead to the development of reversible male contraceptives that work in a short span of time.