The Ca2+-activated K+ current of human sperm is mediated by Slo3

Sperm are equipped with a unique set of ion channels that orchestrate fertilization. In mouse sperm, the principal K+ current (I-KSper) is carried by the Slo3 channel, which sets the membrane potential (V-m) in a strongly pH(i)-dependent manner. Here, we show that I-KSper in human sperm is activated weakly by pH(i) and more strongly by Ca2+. Correspondingly, V-m is strongly regulated by Ca2+ and less so by pH(i). We find that inhibitors of Slo3 suppress human I-KSper, and we identify the Slo3 protein in the flagellum of human sperm. Moreover, heterologously expressed human Slo3, but not mouse Slo3, is activated by Ca2+ rather than by alkaline pH(i); current-voltage relations of human Slo3 and human IKSper are similar. We conclude that Slo3 represents the principal K+ channel in human sperm that carries the Ca2+-activated I-KSper current. We propose that, in human sperm, the progesterone-evoked Ca2+ influx carried by voltage-gated CatSper channels is limited by Ca2+-controlled hyperpolarization via Slo3.