Efficient and targeted sperm motility is crucial for the reproductive success of animals. To regulate their motility, sperm cells utilize a highly conserved signaling pathway involving several steps: hyperpolarization of the flagellar membrane, alkalinization of the sperm cytosol, increased cAMP production, and subsequent activation of the CatSper Ca2+ channel driving chemotaxis.

In this pathway, alkalinization of the sperm cytosol acts as a critical intracellular messenger controlling the onset of motility. A key player in controlling sperm alkalinization is the Na+/H+ exchanger, SLC9C1. This sperm-specific transporter has been shown to be activated following membrane hyperpolarization, causing an increase in intracellular pH and triggering sperm motility.

One remarkable feature of the SLC9C1 transporter is that, just like voltage-gated ion channels, it contains a voltage-sensing domain (VSD), making it unique and the only known transporter to be regulated by voltage-sensing domains. But despite its importance, the molecular basis of SLC9C1 voltage activation remained unclear.

Two recent studies, published in Nature, provide important insights into the architecture and inner workings of this unique voltage-gated transporter. Using cryo-EM to analyze the structure of SLC9C1, researchers found that its voltage-sensing domains contain very long S4 helices and are arranged in an unusual configuration around the SLC9C1 homodimer. When inactive, the transporter is accessible to Na+ binding (which is consistent with Na+-induced currents measured by SSM-based electrophysiology), but its ion-exchange activity is prevented due to an internal constriction by the intracellular helix connected to S4. The authors propose that upon hyperpolarization, and in the presence of cAMP, the S4 segment moves down (as in NaV channels), removing this constriction and enabling Na+/H+ exchange.

The way the VSD is coupled to the SLC9C1 transporter is unprecedented and provides a platform for creating new synthetic proteins that can be regulated by voltage. These findings position SLC9C1 as an interesting target for treating male infertility and could also open new avenues for the development of innovative male contraceptives.

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Find the original articles here: Yeo et al. and Kalienkova et al.

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