On the cellular mechanisms by which the bicarbonate ion mediates the extragenomic action of progesterone on human spermatozoa

Progesterone exerts an extragenomic action on human spermatozoa, inducing a rapid calcium transient in the acrosomal domain of these cells and enhancing their potential for fertilization. This response is known to exhibit an absolute dependence on the presence of extracellular bicarbonate, although the mechanisms underlying this interaction are not understood. In this study, bicarbonate was found to exert a dose-dependent impact on the ability of progesterone to promote sperm-oocyte fusion in the absence of any collateral effect on sperm motility. The loss of sperm function in bicarbonate-free medium was associated with a failure to produce reactive oxygen species, an impaired capacity to exhibit redox-associated changes in tyrosine phosphorylation, and an apparent incapacity to generate normal calcium transients on exposure to progesterone. These defects were not related to a cAMP deficiency but were associated with a significant fall in intracellular pH. If cytosolic pH was chemically buffered into the normal range, then the spermatozoa regained every element of their response to progesterone. These results emphasize the importance of an alkaline intracellular milieu for the extragenomic action of progesterone on human spermatozoa and stress the fundamental difference between intracellular and extracellular sources of bicarbonate in maintaining the proton balance within such cells.