How Progesterone Excites Sperm

Ben -   Also this week, a pair of papers in the journal Nature have shed some light on how human sperm cells react to the presence of progesterone, and this could lead to a whole new type of contraceptive.  Steve Publicover, from the School of Biosciences at the University of Birmingham, penned a "News and Views" article linking the findings of these papers, and explained the implications to me...

Steve -   It's been known for more than 20 years now that progesterone, female hormone progesterone - which is produced by the cells that surround the oocyte and they help it to mature and they're still surrounding it after it's been ovulated, so that the egg probably is descending the oviduct, surrounded by a haze of progesterone.  So people looked at this ages ago and discovered that progesterone induces a very rapid response in human sperm virtually instantly in as much one can detect.  The primary mediator of that seems to be a very sudden rise in intracellular calcium concentration, which is an intracellular message.  That was interesting for a number of reasons partly because it clearly had potential significance for fertilisation, and also, because it was not what one we expected steroids, like progesterone, to do.  But what we did find out in the meantime was that there is very good reason for thinking progesterone matters in fertilisation.  It regulates all sorts of things that we know are really important and at last they've given us a clear precise mechanistic step involved in that whereas up until now, it's been a black box virtually.

Ben -   So the sperm comes into contact with progesterone.  What's the next stage?  What actually happens?

Steve -   Well what progesterone does is induce an increase in the intracellular concentration of calcium ions which are normally kept in cells very, very low.  The cells spend quite a lot of energy mopping calcium up and pumping it out, and keeping it very low.  Rises in calcium concentration are used in every cell we know about as a conveyor of information, the size of the rise, and the shape of the rise in terms of its kinetics, things like that.  In sperm, certainly, calcium is very, very important for controlling how they swim and controlling a particular secretion event that they do called the acrosome reaction.  Progesterone is there as the sperm approach the egg, it may actually be there at very low concentrations in other places as well, but certainly, as the sperm swims right up to the egg, it's going to hit a wall of very high concentrations.  It seems to switch on all sorts of things, but progesterone is like a real sort of wake up call.  It presses a button, the sperm starts doing things.

Ben -   So, the presence of progesterone causes this sudden influx of calcium ions or at least a lack of pumping it out and that obviously is a key stage in changing the behaviour of the sperm cells.

Steve -   Yes.  We've known that the signal, the changing calcium concentration, was there for ages because there are techniques in measuring concentration in cells which are optical and therefore, they've been quite nice for applying to sperm because the fact that sperm are small and tend to move about a bit, doesn't stop you making the measurements.  One of the things that's really key in this, is what's in the Lishko and Kirichok paper, that they developed a technique for applying electrophysiological methods, methods that are used normally in recording the flux of ions across the membranes of nerve cells.  They managed to apply it to sperm which are an order of magnitude or so smaller and very, very difficult for various technical reasons to apply these techniques to.  They made it work, which meant they could actually measure a flow of ions across the cell membrane.  Doing that allowed them to be much more precise to characterise what was going on and to actually identify the fact that progesterone was activating a specific type of protein ion channel in the sperm membrane.

Ben -   Does this particular membrane channel have any other role that we're aware of?  Is it normally functioning in a very low level and then just gets ramped up by progesterone or is it exclusively for this purpose?

Steve -   Up until now, we knew it was there and we knew it was exclusively expressed in sperm.  So, the channel is called CatSper because it's a cat-ion channel and it's only expressed in sperm.  We knew from various experiments that have also been done on mice that functioning of this channel is very important in regulating the way the sperm swim, and if you produce mice where the gene that codes for this channel has been knocked out, they're still fairly healthy because the only thing that's not going to be working normally is the sperm.  The sperm look okay and they can move and they can swim, but they can't undergo a specific change in the way they swim which is called hyperactivation.  It's a much more aggressive way of swimming which is switched on as they approach the egg and it seems to be there to provide a kind of added power to get them through the layers that surround the egg in order that they can get right through and do the fusion event.  In mice that haven't got this protein, they can't do that change in motility and the result is they're completely sterile.

Ben -   So now that we've shed a bit more light on this mechanism, can we start to find ways to use it to our own purposes?  Could this be a new contraceptive?

Steve -   I think in principle, it certainly could be.  It's an enormous opportunity because this is completely specific to sperm and nothing else.  If you can produce a drug that hits this channel and nothing else, then you've got a perfect contraceptive.  The channel itself belongs to a family which is quite a large one, of voltage operated channels of various sorts, and certainly, some of the other ones are quite similar in their structure.  So finding a drug that's really specific to CatSper may turn out to be quite difficult, but I guess in principle, it certainly should be doable.  If that could be done, then you could certainly produce a drug that would give you a really nice male contraceptive.

Ben -   Steve Publicover from Birmingham University.  You can read Steve's news and views article, along with the two papers he discusses, in this week's edition of the journal Nature.