Dual Sensing of Physiologic pH and Calcium by EFCAB9 Regulates Sperm Motility

Cell. 2019 May 30;177(6):1480-1494.e19. doi: 10.1016/j.cell.2019.03.047. Epub 2019 May 2.


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 Ca2+ signaling nanodomains along the sperm tail. Here, we identify EF-hand calcium-binding domain-containing protein 9 (EFCAB9) as a bifunctional, cytoplasmic machine modulating the channel activity and the domain organization of CatSper. Knockout mice studies demonstrate that EFCAB9, in complex with the CatSper subunit, CATSPERζ, 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 CATSPERζ 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.

Keywords: Ca(2+) sensor; Ca(2+) signal transduction; Ca2(+) channel; CatSper; male fertility; pH sensing; sperm motility.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Calcium Channels / metabolism
  • Calcium Signaling / physiology
  • Calcium-Binding Proteins / metabolism*
  • Calcium-Binding Proteins / physiology
  • Cell Line
  • Cell Membrane / metabolism
  • Fertility
  • HEK293 Cells
  • Humans
  • Hydrogen-Ion Concentration
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Sperm Motility / physiology*
  • Spermatozoa / metabolism


  • CATSPER1 protein, human
  • Calcium Channels
  • Calcium-Binding Proteins
  • Calcium