EFCAB9 is a pH-Dependent Ca2+Sensor that Regulates CatSper Channel Activity and Sperm Motility

Summary Varying pH of luminal fluid along the female reproductive tract is a physiological cue that modulates sperm motility. CatSper is a sperm-specific, pH-sensitive calcium channel essential for hyperactivated motility and male fertility. Multi-subunit CatSper channel complexes organize linear Ca 2+ signaling nanodomains along the sperm tail. Here, we identify EF-hand calciumbinding domain-containing protein 9 (EFCAB9) as a dual function, cytoplasmic machine modulating the channel activity and the domain organization of CatSper. Knockout mice studies demonstrate that EFCAB9, in complex with the CatSper subunit, CAT SPERζ, is essential for pH-dependent and Ca 2+ sensitive activation of the CatSper channel. In the absence of EFCAB9, sperm motility and fertility is compromised and the linear arrangement of the Ca 2+ signaling domains is disrupted. EFCAB9 interacts directly with CATSPERζ in a Ca 2+ dependent manner and dissociates at elevated pH.These observations suggest that EFCAB9 is a long-sought, intracellular, pH-dependent Ca 2+ sensor that triggers changes in sperm motility. Highlights Efcab9 encodes an evolutionarily conserved, sperm-specific EF-hand domain protein Efcab9 -deficient mice have sperm motility defects and reduced male fertility EFCAB9 is a pH-tuned Ca 2+ sensor for flagellar CatSper Ca 2+ channel EFCAB9 is a dual function machine in gatekeeping and domain organization of CatSper