Comparative genomic analysis suggests that the sperm-specific sodium/proton exchanger and soluble adenylyl cyclase are key regulators of CatSper among the Metazoa.

Abstract

Background: CatSper is a sperm-specific calcium ion (Ca²⁺) channel, which regulates sperm flagellar beating by tuning cytoplasmic Ca²⁺ concentrations. Although this Ca²⁺ channel is essential for mammalian fertilization, recent bioinformatics analyses have revealed that genes encoding CatSper are heterogeneously distributed throughout the eukaryotes, including vertebrates. As this channel is activated by cytoplasmic alkalization in mammals and sea urchins, it has been proposed that the sperm-specific Na⁺/H⁺ exchanger (sNHE, a product of the SLC9C gene family) positively regulates its activity. In mouse, sNHE is functionally coupled to soluble adenylyl cyclase (sAC). CatSper, sNHE, and sAC have thus been considered functionally interconnected in the control of sperm motility, at least in mouse and sea urchin.

Results: We carried out a comparative genomic analysis to explore phylogenetic relationships among CatSper, sNHE and sAC in eukaryotes. We found that sNHE occurs only in Metazoa, although sAC occurs widely across eukaryotes. In animals, we found correlated and restricted distribution patterns of the three proteins, suggesting coevolution among them in the Metazoa. Namely, nearly all species in which CatSper is conserved also preserve sNHE and sAC. In contrast, in species without sAC, neither CatSper nor sNHE is conserved. On the other hand, the distribution of another testis-specific NHE (NHA, a product of the SLC9B gene family) does not show any apparent association with that of CatSper.

Conclusions: Our results suggest that CatSper, sNHE and sAC form prototypical machinery that functions in regulating sperm flagellar beating in Metazoa. In non-metazoan species, CatSper may be regulated by other H⁺ transporters, or its activity might be independent of cytoplasmic pH.