Researchers at Stockholm University have uncovered the hidden complexities of how sperm go from passive bystanders to active swimmers. This conversion is a critical step in the fertilization journey, and it depends on the activation of a unique ion transporter.
Imagine the sperm as tiny explorers trying to reach the ultimate treasure, the egg. They don’t have a map, but they use something even more extraordinary: chemo-attractants. These are chemical signals released by the egg that act as siren calls, directing and activating the sperm. When these signals bind to receptors on the surface of sperm, it triggers a series of events that initiate their movement toward the egg. And in this complex situation, a key player is a protein known as “SLC9C1”.
It is found exclusively in sperm cells and is not normally activated. However, when chemo-attractants interact with the sperm’s surface, everything changes.
SLC9C1 acts as a highly sophisticated exchange system. It swaps protons from inside the cell for sodium ions from outside, temporarily creating a less acidic environment within the sperm. “This change in the internal environment increases sperm motility.”
David Drew, Professor of Biochemistry at Stockholm University
Activation of SLC9C1 is driven by voltage changes that occur when the chemoattractant binds to sperm. To accomplish this, SLC9C1 uses a unique feature called a voltage-sensing domain (VSD). Typically, VSD domains are associated with voltage-gated ion channels. But in the case of SLC9C1, it’s something truly exceptional among transporters.
Researchers, led by David Drew, have unraveled the mystery behind the inner workings of SLC9C1 and provided the first example of activation of a transporter’s voltage-sensing domain and its association with an unusually long voltage-sensing (S4) helix.
“The VSD domain responds to changes in voltage by pushing its rod-like S4 helix inward. This clears the way for ion exchange by SLC9C1, ultimately initiating sperm motility,” said David Drew.
“Transporters work very differently than channels, and as such, the VSD interacts with sperm proteins in a way we’ve never seen before, or even imagined. It’s exciting to see how nature has done it, and perhaps in the future. “We can learn from this to create synthetic proteins that voltage can be activated by or block this protein to create novel male contraceptives,” notes David Drew.
The research was made possible by funding from the European Research Council (ERC) grant exchange.
Yeo, H., etc. (2023). Structure and electromechanical coupling of a voltage-gated Na+/H+ exchanger. the nature. doi.org/10.1038/s41586-023-06518-2.