Soumya Shraddhya Paul, Amity University Noida
From the time pH first came into existence it has been playing a really important role in nature. Researchers have seen that, for our body to work properly it’s very important to maintain the intracellular pH. Another very fascinating term related to this is human voltage-gated proton channels (hHv1) which are important in many of the biological processes that happen in our body. One of those processes is human sperm capacitation, recently to show this process scientist designed a peptide inhibitor (C6) of the channel to show H+ efflux in hHv1 which causes intracellular alkalinization required for human sperm capacitation and is also needed for human neutrophils to maintain cytoplasmic pH during the respiratory burst to allow reactive oxygen species (ROS) production.
Albumin is one of the most abundant proteins present in the interstitial fluid of the human body i.e., 7-30 mg/mL. Hence, researchers wondered about its relationship with hHv1due to its contrasting levels in semen (1mg/ml, 15 µM) and uterine fluid (34 mg/mL, 500 µM). It was also noted that during IVF (in vitro fertilization) the success rate was higher when the semen solution was supplemented with albumin (Alb). Alb was also seen to cause deleterious systemic inflammatory responses mediated by neutrophils after cardiopulmonary bypass and in periodontal disease.
Brief About the Study:
In this study, researchers showed that Alb binds with hHv1 which results in the activation of the channel which increases the open probability as well as the H+ current. This results in human sperm capacitation as well in neutrophils; this results in increased peak levels of ROS release sustains ROS production during the respiratory burst and stimulates the release of proteases in response to immune stimulation.
Here to understand the binding stoichiometry Hill’s coefficient was used which helps to note the changes in H+ current based on the Alb dose. It was noted that this result was one Alb per channel based on single-molecule total internal reflection fluorescent (smTIRF) microscopy. Alb binds with hHv1 on the external residues. To show this, they used a voltage sensor (S3-S4 loops) and this linked the third and fourth transmembrane segment. After this modeling was done using molecular dynamics (MD) which showed two binding sites, formed by residues in Alb domain II (DII) for the two S3-S4 loops in each hHv1channel. The structural model of Alb-hHv1 macromolecule showed an electrostatic gating modification mechanism through which binding happened.
Results:
Capacitation is a process that happens in the female reproductive tract, as the pH rises because the female reproductive tract is more alkaline, this stimulates Ca2+ influx which causes the mobility to change. This helps in the fertilization of the oocyte by the sperm, here it was noticed that Alb activates the hHv1 channel in live human sperm by recording proton currents in mature non-capacitated spermatozoa.
Alb was also seen to stimulate hHv1 in neutrophils, a type of white blood cell that elates ROS (Reactive Oxygen Species) production and elastase release which is a mechanism that helps to kill bacteria. Alb also helps in the activation of cloned hHv1 by changing the voltage dependency of gating, like mentioned before Alb binds with the external S3-S4 loop of the hHv1. Due to its increased affinity, one Alb binds only to one dimeric hHv1 channel lastly a proposed model was prepared using the NAMD program using MD simulation of the Alb-hHv1 complex.
Conclusion
Through this study, it was shown that Alb plays a really important role in sperm capacitation, it also helps modulate the innate immune system via hHv1, a model was also developed using this study of Alb-hHv1 and a proposed mechanism of Alb acting like an electrostatic gate modifier was given.
Also read: Role of ERα signalling in Mammary Gland Morphogenesis
References:
- Zhao, R., Dai, H., Arias, R.J. et al. Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils. Nat Commun 12, 3855 (2021). https://doi.org/10.1038/s41467-021-24145-1
About Author:
Soumya Shraddhya Paul is an undergrad biotechnology student who worked in building 3D prosthetics in Base Hospital Delhi Cantt, and holds a key interest in nutraceuticals and enzymology.
Some of her publications at BioXone are:
- https://bioxone.in/news/worldnews/understanding-b-cell-genomics-to-fight-against-covid-19/
- https://bioxone.in/news/worldnews/the-current-ebola-epidemic-comes-to-an-end/
Social Media Info: www.linkedin.com/in/soumya-shraddhya-paul-858229203
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