Polarized PtdIns(4,5)P₂ distribution mediated by a voltage-sensing phosphatase (VSP) regulates sperm motility.

The voltage-sensing phosphatase (VSP) is a unique protein that shows voltage-dependent phosphoinositide phosphatase activity. Here we report that VSP is activated in mice sperm flagellum and generates a unique subcellular distribution pattern of PtdIns(4,5)P₂ Sperm from VSP^-/- mice show more Ca²⁺ influx upon capacitation than VSP^+/- mice and abnormal circular motion. VSP-deficient sperm showed enhanced activity of Slo3, a PtdIns(4,5)P₂-sensitive K⁺ channel, which selectively localizes to the principal piece of the flagellum and indirectly enhances Ca²⁺ influx. Most interestingly, freeze-fracture electron microscopy analysis indicates that normal sperm have much less PtdIns(4,5)P₂ in the principal piece than in the midpiece of the flagellum, and this polarized PtdIns(4,5)P₂ distribution disappeared in VSP-deficient sperm. Thus, VSP appears to optimize PtdIns(4,5)P₂ distribution of the principal piece. These results imply that flagellar PtdIns(4,5)P₂ distribution plays important roles in ion channel regulation as well as sperm motility.

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