Membrane dynamics occurring during capacitation of mammalian spermatozoa

Immediately after ejaculation, mammalian spermatozoa are unable to fertilize the oocyte and gain their full fertilizing ability only after they reside hours or days (depending on the species) within the female genital tract. The process that drives male gametes to became fertile, the capacitation, implies the transduction of several biochemical messages, leading to the modification of virtually all the components of spermatozoa: the cytoskeleton reorganizes its architecture, the protein phosphorylation pattern changes, a new kind of motility (the hyperactivated motility) onsets, the intracellular pH decreases and the intracellular calcium concentration rises, the plasma membrane (PM) and the outer acrosome membrane (OAM) deeply change their architecture. In particular, this last event has attracted the attention of several Researchers due to the importance of sperm membranes reorganization in allowing the fusion of PM and OAM, thus making possible the exocytosis of acrosome content (acrosome reaction, AR), a key event preparatory to fertilization. It is currently known that sperm membranes are highly dynamical asymmetrical structures. Indeed the composition of inner and outer leaflet of bilayer is different and it is possible to recognize different levels of organization, from microdomains to macrodomanis, in their arrangement. In particular, the plasma membrane over spermatozoa head consists of areas characterized by specific chemical- physical and functional proprieties: the apical ridge area, the pre-equatorial area, the equatorial area and the post-equatorial area. The apical ridge is involved in sperm-zona pellucida recognition and binding, the pre-equatorial surface is the site where the fusion between PM and OAM takes place during AR and the equatorial surface area participates to the sperm adhesion and fusion with female gametes, at the moment of fertilization. In turn, each domain is a puzzle of specialized areas, the microdomains, that are small lipid ordered portions of membrane characterized by a high concentration of cholesterol, sphingomyelin, gangliosides, phospholipids with saturated long-chain acyl chains, and proteins such as GPI anchored proteins, caveolin and flotillin. During capacitation either macrodomains and microdomains undergo deep modifications, with important consequence on function of several molecules active in signal transduction. Recently, it has been showed that sperm membrane dynamics are under control of a finely regulated dialogue between activating and inhibiting agents. In particular, it was found that the high level of bicarbonate, present within the upper female genital tract or in cultural media, activate the lipid scrambling on anterior areas of sperm head, thus allowing the cholesterol extraction by extracellular proteins and, as a consequence, determining the increase in PM and OAM ability to fuse each other (the so called "fusoigenicity"). On the contrary, molecules belonging to the endocannbinoid system exert an inhibitory activity acting either on type-1 cannabinoid (CB1) receptor and on transient receptor potential cation channel 1 (TRPV1). Indeed they modulate, respectively, the cAMP intracellular concentration and the ionic composition of cytosol. Interestingly bicarbonate and endocannbinoids control the dynamics of membrane reorganization, and the membrane reorganization implies a functional relocalization of important molecules involved in bicarbonate and endocannabinoid-related signal transduction.