Cell biology of reproduction and membranes: how sperm become able to fertilize and how membrane lipids regulate cell function

The concept of pathway compartmentalization extends into signaling in our investigations of specialized membrane domains known as “membrane rafts.” These dynamic regions are highly enriched in sterols and sphingolipids, as opposed to phospholipids. Rafts are uniquely important to the processes through which sperm mature in the epididymis and in the female tract, as they acquire the ability to fertilize. We identified micron-scale segregations of sterols and the ganglioside G_M1 in the sperm plasma membrane, as well as 3 distinct and highly reproducible sub-types of nanometer-scale rafts. Quantitative and shotgun proteomics and lipid biochemistry have defined these sub-types and identified targets for our current functional investigations.

For example, we recently showed how the physiological stimulus of sterol efflux enables sperm to fertilize, through the activation of phospholipase B. New models of sperm-egg interaction suggest that the sperm plasma membrane begins to fuse with the underlying acrosomal membrane during transit through the cumulus cells—long before they reach the zona pellucida. Our data showing activation of PLB provide a mechanism for how sterol efflux could lead to the necessary point fusions.

We also study how the ganglioside G_M1 controls the process of acrosome exocytosis by regulating transient calcium fluxes that enable membrane fusion.  Using approaches from cell biology, pharmacology, genetics, and ion channel physiology, we have recently defined a specific interaction through which G_M1 regulates calcium transients through the R-type, CaV 2.3 channel. Our studies of sperm are now leading us to examine the broader issue of how membrane lipids can regulate the activity of resident channels, thereby controlling cell function.