All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility

TLDR

Mammalian sperm must acquire hyperactivated motility to penetrate the cumulus and zona pellucida, a process known to involve CatSper1 and CatSper2 but not yet understood for CatSper3 and CatSper4. The forceful asymmetric motion of hyperactivated spermatozoa requires Ca²⁺ entry into the sperm tail via an alkalinization‑activated, voltage‑sensitive, Ca²⁺‑selective current (I_CatSper). Disruption of CatSper3 or CatSper4 eliminates I_CatSper, hyperactivated motility, and male fertility while sparing spermatogenesis and initial motility, and protein interaction studies show that all four CatSper proteins are specialized flagellar components.

Abstract

Mammalian spermatozoa become motile at ejaculation, but before they can fertilize the egg, they must acquire more thrust to penetrate the cumulus and zona pellucida. The forceful asymmetric motion of hyperactivated spermatozoa requires Ca 2+ entry into the sperm tail by an alkalinization-activated voltage-sensitive Ca 2+ -selective current ( I CatSper ). Hyperactivation requires CatSper1 and CatSper2 putative ion channel genes, but the function of two other related genes ( CatSper3 and CatSper4 ) is not known. Here we show that targeted disruption of murine CatSper3 or CatSper4 also abrogated I CatSper , sperm cell hyperactivated motility and male fertility but did not affect spermatogenesis or initial motility. Direct protein interactions among CatSpers, the sperm specificity of these proteins, and loss of I CatSper in each of the four CatSper −/− mice indicate that CatSpers are highly specialized flagellar proteins.