Wrath of the wraiths of CatSper3 and CatSper4.

T he spermatozoon is a marvelous machine designed by nature for the single task of finding an oocyte, delivering its genetic payload, and initiating the formation of a new embryo. Like many of the most specialized and sophisticated mechanical creations of humans, the sperm is fitted with unique components and stripped of unneeded hardware, including most of its biosynthetic equipment. As a consequence, for mice, humans, and other mammals, the male stores sperm in a quiescent state to conserve irreplaceable resources. Upon release into the female reproductive tract, the ejaculated sperm ‘‘awaken’’ to begin the obligatory maturational sequence, called ‘‘capacitation,’’ that is required to complete their vital mission. Several of the components of capacitation require extracellular Ca2 . These include an early activation of sperm motility, thought to be necessary for entry of sperm into the oviduct, and a subsequent peculiar ‘‘hyperactivation’’ of motility, thought to be necessary for sperm to penetrate the cumulus oophorus and zona pellucida that surround the oocyte (1, 2). Our understanding of the Ca2 requirement for hyperactivation has increased greatly since the discovery of the CatSpers (3–5), a unique family of four sperm-specific ion channel proteins. In landmark work last year (6), the Clapham laboratory reported successful whole-cell patch-clamp recording of a Ca2 -selective, alkalinepromoted current that is present in wildtype sperm but absent in sperm from CatSper1 / mice. In this issue of PNAS, Qi et al. (7) reveal that all four CatSper proteins are required for sperm to form the flagellar ion channels that provide the route of entry for the Ca2 that is needed for hyperactivation. The lack of functional CatSper channels prevents hyperactivation and produces the male infertility phenotype shared by mice carrying mutations that prevent transcription of full-length Catsper1 (4), CatSper2 (3), or CatSper3 or CatSper4 (7).