AsianScientist (Jan. 24, 2025) – Electricity is often a conductor to an orchestra of biological processes in our bodies. In cells, the separation of charges across the cell membrane, creates a tiny voltage—like a battery—called the membrane potential. This electrical signal enables neurons to communicate, triggers muscles to contract and even guides the maturation of young sperm.
Scientists from Osaka University have discovered a protein that takes cues from changes in the membrane potential to prepare a sperm for fertilization. Their finding, published in Nature Communications, adds an important piece to the puzzle of sperm development and could improve treatments for male infertility.
Sperms get fine-tuned as they travel through the male reproductive system. A key adjustment involves altering the lipid composition of their cell membranes, a process regulated by enzymes activated at precise stages.
Voltage-sensing phosphatase (VSP) is one such enzyme. It removes phosphate molecules from lipids called phosphoinositides (PIPs) in response to voltage changes. VSP does this with the help of its unique structure: a voltage-sensor domain (VSD) for detecting membrane potential, a phosphatase domain (PD) for enzymatic activity and a VSD-PD linker connecting them.
In an earlier study in mice, the research team found that VSP creates a specific lipid gradient along the sperm tail, which is essential for their ability to swim. While VSP’s voltage-sensitive enzyme function has been demonstrated in vertebrates like zebrafish, frogs, and chickens, studying it in mammals has been tricky.
To overcome this, the researchers turned to an intriguing method for studying complex proteins: a heterologous expression system. Similar to how marine scientists study ocean fish in lab aquariums, the team expressed mouse VSP in frog egg cells—providing a controlled and simplified system to observe its voltage-sensing behaviour.
Using a modified version of VSP for enhanced detection and microelectrodes for precise measurements, they discovered that VSP activates at approximately -30 millivolts, lower than the resting potential of immature sperm.
To understand how VSP’s voltage-dependent activity affects sperm maturation, they engineered three mouse models with distinct mutations: one lacking voltage-sensing ability, another disrupting the link between voltage-sensing to enzyme activity and a third with slightly altered voltage-sensitivity. The first two mutations blocked VSP expression, while altering VSP’s voltage activation range compromised sperm motility.
“Our findings show that in developing sperm, VSP responds to electrical signals by promoting appropriate maturation of the cell membrane,” said Yasushi Okamura, senior author and professor in the Department of Physiology at Osaka University.
This study is the first to confirm the voltage-dependent enzymatic activity of mammalian VSPs. Since proper sperm development is essential to male fertility, targeting VSP function could become a novel strategy for clinical interventions.
Looking ahead, the authors believe that deeper insights into how electrical signals regulate enzyme activity could unlock breakthroughs in cell development.
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Source: Osaka University ; Image: Shelly Liew/ Asian Scientist Magazine
The article can be found at The significance of electrical signals in maturing spermatozoa for phosphoinositide regulation through voltage-sensing phosphatase.
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