Ca2+ Signals Generated by CatSper and Ca2+ Stores Regulate Different Behaviors in Human Sperm

[Ca2+](i) signaling regulates sperm motility, enabling switching between functionally different behaviors that the sperm must employ as it ascends the female tract and fertilizes the oocyte. We report that different behaviors in human sperm are recruited according to the Ca2+ signaling pathway used. Activation of CatSper (by raising pH(i) or stimulating with progesterone) caused sustained [Ca2+](i) elevation but did not induce hyperactivation, the whiplash-like behavior required for progression along the oviduct and penetration of the zona pellucida. In contrast, penetration into methylcellulose (mimicking penetration into cervical mucus or cumulus matrix) was enhanced by activation of CatSper. NNC55-0396, which abolishes CatSper currents in human sperm, inhibited this effect. Treatment with 5 mu M thimerosal to mobilize stored Ca2+ caused sustained [Ca2+](i) elevation and induced strong, sustained hyperactivation that was completely insensitive to NNC55-0396. Thimerosal had no effect on penetration into methylcellulose. 4-Aminopyridine, a powerful modulator of sperm motility, both raised pHi and mobilized Ca2+ stored in sperm (and from microsomal membrane preparations). 4-Aminopyridineinduced hyperactivation even in cells suspended in Ca2+-depleted medium and also potentiated penetration into methylcellulose. The latter effect was sensitive to NNC55-039, but induction of hyperactivation was not. We conclude that these two components of the [Ca2+](i) signaling apparatus have strikingly different effects on sperm motility. Furthermore, since stored Ca2+ at the sperm neck can be mobilized by Ca2+-induced Ca2+ release, we propose that CatSper activation can elicit functionally different behaviors according to the sensitivity of the Ca2+ store, which may be regulated by capacitation and NO from the cumulus.