The Ca ²⁺-activated K ⁺ current of human sperm is mediated by Slo3

Abstract

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 Ca ²⁺. Correspondingly, V _m is strongly regulated by Ca ²⁺ 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 Ca ²⁺ rather than by alkaline pH _i; current–voltage relations of human Slo3 and human I _KSper are similar. We conclude that Slo3 represents the principal K ⁺ channel in human sperm that carries the Ca ²⁺-activated I _KSper current. We propose that, in human sperm, the progesterone-evoked Ca ²⁺ influx carried by voltage-gated CatSper channels is limited by Ca ²⁺-controlled hyperpolarization via Slo3.

DOI: http://dx.doi.org/10.7554/eLife.01438.001

eLife digest

A sperm that has been ejaculated into the female reproductive tract must complete a number of tasks to pass on its genes to the next generation. First it must travel along a meandering route to encounter an egg, before pushing through a jelly-like coating that surrounds the egg and then, finally, fusing with the egg’s surface membrane. In order to complete these steps and fertilise the egg, a sperm must undergo a process called ‘capacitation’. This process, and a variety of other sperm functions, involves the controlled flux of positive ions into and out of the sperm via specific ion channels that are located in the cell membrane.

The properties of the ion channels that allow protons and calcium ions to move into and out of human sperm are well understood, but less is known about the channels that control the movement of potassium ions. In mice, a channel called Slo3 allows potassium ions to flow out of the sperm and makes the membrane voltage of these cells more negative. Also, in mice, this channel is essential for the sperm to function correctly, and for fertilization. However, in humans, it is unclear if the Slo3 channel is present in sperm and if it performs the same role.

Now, Brenker et al. have shown that the flow of potassium ions out of human sperm occurs via the Slo3 channel, and that human Slo3 is responsible for setting the membrane voltage of these cells. However, whereas the mouse Slo3 channel is opened in response to a decrease in the concentration of protons within the sperm (i.e., an increase of the pH inside the cell), human Slo3 is largely controlled by changes in the levels of calcium ions. An increase in the calcium concentration within the cell opens the human Slo3 channel, more than a decrease in the proton concentration does.

Altogether, Brenker et al. identify Slo3 as the principal potassium channel in human sperm and reveal more fundamental differences between human sperm and mouse sperm. Thereby, this work further stresses the need to be cautious about using mice as a model of male fertility in humans.

DOI: http://dx.doi.org/10.7554/eLife.01438.002