Hyperactivated sperm motility driven by CatSper2 is required for fertilization

TLDR

Elevated sperm Ca²⁺ triggers hyperactivated motility, yet the intracellular Ca²⁺ source remains unknown and the role of voltage‑gated channels in this process is unclear, despite their presence in sperm and the association of motility with infertility. Loss of the sperm‑specific channel CatSper2 abolishes hyperactivated motility and renders males infertile, even though forward velocity and capacitation markers are normal, indicating that CatSper2‑driven hyperactivation is essential for penetration of the egg’s extracellular matrix.

Abstract

Elevations of sperm Ca 2+ seem to be responsible for an asymmetric form of motility called hyperactivation, which is first seen near the time of fertilization. The mechanism by which intracellular Ca 2+ concentrations increase remains unknown despite considerable investigation. Although several prototypical voltage-gated calcium channels are present in spermatozoa, they are not essential for motility. Furthermore, the forward velocity and percentage of motility of spermatozoa are associated with infertility, but their importance relative to hyperactivation also remains unknown. We show here that disruption of the gene for a recently described sperm-specific voltage-gated cation channel, CatSper2, fails to significantly alter sperm production, protein tyrosine phosphorylation that is associated with capacitation, induction of the acrosome reaction, forward velocity, or percentage of motility, yet CatSper2 –/– males are completely infertile. The defect that we identify in the null sperm cells is a failure to acquire hyperactivated motility, which seems to render spermatozoa incapable of generating the “power” needed for penetration of the extracellular matrix of the egg. A loss of power is suggested also by experiments in which the viscosity of the medium was increased after incubation of spermatozoa in normal capacitating conditions. In high-viscosity medium, CatSper2-null spermatozoa lost the ability to swim forward, whereas wild-type cells continued to move forward. Thus, CatSper2 is responsible for driving hyperactivated motility, and, even with typical sperm forward velocities, fertilization is not possible in the absence of this highly active form of motility.