Researchers have explored the roles that albumin and human voltage-gated proton channels, called hHv1, play in triggering fertilisation.
Human voltage-gated proton channels (hHv1) are membrane proteins that open following the depolarisation of a cell. In other words, they are ion channels that control intracellular pH and regulate protein function by extruding protons from cells in response to changes in membrane potential.
hHv1 channels contain voltage-sensing domains (VSDs), which are functional modules that regulate the opening and closing of the ion channels. VSDs comprise of four transmembrane helical segments – S1, S2, S3 and S4. The voltage sensitivity of hHv1 is mainly conferred by the S4 helix. hHv1 is the main pathway for proton efflux in sperm, allowing capacitation. This is one of the final steps in the maturation of the spermatozoa and is required for the fertilisation of an oocyte – the female egg.
Albumin (Alb) makes up around half of all human blood plasma proteins. The main function of Alb is to keep fluid moving throughout the body by maintaining colloid osmotic pressure. This is a form of osmotic pressure, induced by proteins in the blood plasma, that moves water molecules back into the circulatory system. Alb is also recognised for the transport of various substances, such as hormones, metabolites and drugs.
Historically, studies have reported that the concentration of Alb in semen is too low to activate hHv1 in sperm. Conversely, high levels of Alb have been documented in uterine fluids – a medium for sperm transport. Notably, it has been recognised that reproductive success increases when in vitro fertilisation (IVF) solutions are implemented with Alb.
Connection between Alb and hHv1
Recently, researchers at the University of California investigated the connection between Alb and hHv1, based on contrasting concentrations of the protein in semen and uterine fluid.
The main findings were as follows:
- Alb acted on hHv1 in human sperm to initiate capacitation.
- Alb activated cloned hHv1 by changing the voltage-dependence of gating.
- Alb bound to the external S3–S4 loop of hHv1.
- One Alb bound to one dimeric hHv1 channel.
- Alb domain II was the principal domain for binding to hHv1.
A proposed model of albumin binding to hHv1 in two orientations showing three Alb domains (DI, DII and DIII) and the two sub-units of a hHv1 channel. The horizonal grey lines indicate the position of the membrane boundary. Image credit: Steve A. N. Goldstein, 2021
Essentially, it was demonstrated that Alb binds directly to hHv1 to activate the channel, in turn increasing the proton current and initiating capacitation in the sperm. It was suggested that two binding sites were formed by residues in the Alb domain II and the S3-S4 loops of each hHv1 channel.
Alb roles in other tissues
For the first time, these findings demonstrate how Alb is required for the activation of hHv1 in sperm to trigger fertilisation. This result is exciting because it suggests that Alb will also operate in many other tissues that express hHv1. It is highly likely that Alb plays critical roles that are not yet recognised, such as in the central nervous system, the heart and cancers of the breast and gastrointestinal tract. Therefore, the implications of this novel research are widespread.
Steve A. N Goldstein, a lead researcher in the project, said: “It is exciting to discover that a common protein has the power to activate the proton channel. This finding suggests new strategies to block or enhance fertility, and to augment or suppress the innate immune response and inflammation.”
Image credit: FreePik kjpargeter
