Nucleoside Triphosphate Diphosphohydrolase-1 Ectonucleotidase Is Required for Normal Vas Deferens Contraction and Male Fertility through Maintaining P2X1 Receptor Function [Cell Biology]

August 25th, 2014 by Kauffenstein, G., Pelletier, J., Lavoie, E. G., Kukulski, F., Martin-Satue, M., Dufresne, S. S., Frenette, J., Ribas Furstenau, C., Sereda, M. J., Toutain, B., Henrion, D., Sullivan, R., Vial, C., Sevigny, J.

In this work we report that Entpd1-/- mice, deficient for the ectonucleotidase nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), produce smaller litters (27% reduction) compared to wild type C57BL6 animals. This deficit is linked to reduced in vivo oocytes fertilization by Entpd1-/- males (61±11% vs. 88±7% for Entpd1+/+). Normal epididymal sperm count, spermatozoa morphology, capacitation and motility and reduced ejaculated sperm number (2.4±0.5 vs. 3.7±0.4 million for Entpd1+/+) pointed on vas deferens dysfunction. NTPDase1 was localized by immunofluorescence in the tunica muscularis of vas deferens. Its absence resulted in a major ATP hydrolysis deficiency as observed in situ by histochemistry and in primary smooth muscle cell cultures. In vitro, Entpd1-/- vas deferens displayed an exacerbated contraction to ATP, a diminished response to its non-hydrolysable analogue abMeATP, and a reduced contraction to electrical field stimulation suggesting an altered P2X1 receptor function with a propensity to desensitize. This functional alteration was accompanied with a 3-fold decrease in P2X1 protein expression in Entpd1-/- vas deferens with no variation in mRNA levels. Accordingly, exogenous nucleotidase activity was required to fully preserve P2X1 receptor activation by ATP in vitro. Our study demonstrates that NTPDase1 is required to maintain normal P2X1 receptor functionality in vas deferens and that its absence leads to impaired peristalsis, reduced spermatozoa concentration in the semen, and eventually reduced fertility. This suggests that alteration of NTPDase1 activity impacts on ejaculation efficacy and male fertility. This work may contribute to unveil causes of infertility and open new therapeutic potentials.
  • Posted in Journal of Biological Chemistry, Publications
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