Direct activation of the proton channel by albumin leads to human sperm capacitation and sustained release of inflammatory mediators by neutrophils

ZHAO, RUIMING; DAI, HUI; ARIAS, RODOLFO J.; DE BLAS, GERARDO A.; ORTA, GERARDO; PAVAROTTI, MARTÍN A.; SHEN, RONG; PEROZO, EDUARDO; MAYORGA, LUIS S.; DARSZON, ALBERTO; GOLDSTEIN, STEVE A. N.

NATURE COMMUNICATIONS

Nature

Año: 2021 vol. 12

2041-1723

uman voltage-gated proton channels (hHv1) extrude protons from cells to compensate forcharge and osmotic imbalances due metabolism, normalizing intracellular pH and regulatingprotein function. Human albumin (Alb), present at various levels throughout the body, regulatesoncotic pressure and transports ligands. Here, we report Alb is required to activatehHv1 in sperm and neutrophils. Dose-response studies reveal the concentration of Alb insemen is too low to activate hHv1 in sperm whereas the higher level in uterine fluid yieldsproton efflux, allowing capacitation, the acrosomal reaction, and oocyte fertilization. Likewise,Alb activation of hHv1 in neutrophils is required to sustain production and release of reactiveoxygen species during the immune respiratory burst. One Alb binds to both voltage sensordomains (VSDs) in hHv1, enhancing open probability and increasing proton current. Acomputational model of the Alb-hHv1 complex, validated by experiments, identifies two sitesin Alb domain II that interact with the VSDs, suggesting an electrostatic gating modificationmechanism favoring the active ?up? sensor conformation. This report shows how sperm aretriggered to fertilize, resolving how hHv1 opens at negative membrane potentials in sperm,and describes a role for Alb in physiology that will operate in the many tissuesexpressing hHv1.