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

SummaryVarying 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 Ca2+ 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 SPER{zeta}, is essential for pH-dependent and Ca2+ sensitive activation of the CatSper channel. In the absence of EFCAB9, sperm motility and fertility is compromised and the linear arrangement of the Ca2+ signaling domains is disrupted. EFCAB9 interacts directly with CATSPER{zeta} in a Ca2+ dependent manner and dissociates at elevated pH.These observations suggest that EFCAB9 is a long-sought, intracellular, pH-dependent Ca2+ sensor that triggers changes in sperm motility.\n\nHighlightsO_LIEfcab9 encodes an evolutionarily conserved, sperm-specific EF-hand domain protein\nC_LIO_LIEfcab9-deficient mice have sperm motility defects and reduced male fertility\nC_LIO_LIEFCAB9 is a pH-tuned Ca2+ sensor for flagellar CatSper Ca2+ channel\nC_LIO_LIEFCAB9 is a dual function machine in gatekeeping and domain organization of CatSper\nC_LI