Contrary to popular belief, the race is not always to the swift. A study by Wilcox and colleagues (1995) found that nearly all human pregnancies result from sexual intercourse during a 6-day period ending on the day of ovulation. This means that the fertilizing sperm could have taken as long as 6 days to make the journey to the oviduct. Although some human sperm reach the ampulla of the oviduct within half an hour of intercourse, these “speedy” sperm may have little chance of fertilizing the egg because they have not undergone capacitation. As the sperm reach the ampulla, they acquire competence—but they lose it if they stay around too long.
The molecular processes of capacitation prepare the sperm for the acrosome reaction and enable the sperm to become hyperactive. Although the details of these processes still await description (they are notoriously difficult to study), two sets of molecular changes are considered to be important:
1. Lipid changes. The sperm cell membrane is altered by the removal of cholesterol by albumin proteins in the female reproductive tract (Cross 1998). The cholesterol efflux from the sperm cell membrane is thought to change the location of its “lipid rafts,” transiently structured domains that often contain signaling and adhesion proteins (Bou Khalil et al. 2006; Gadella et al. 2008). Lipid rafts are originally located throughout the sperm cell membrane, but after cholesterol efflux they are clustered over the anterior sperm head and appear to enhance the ability to bind to the zona pellucida surrounding the egg (Watanabe et al. 2017). Moreover, the outer acrosomal membrane of the sperm changes and comes into contact with the sperm cell membrane in a way that prepares it for the acrosome reaction (Tulsiani and Abou-Haila 2004).
2. Protein changes. Particular proteins or carbohydrates on the sperm surface are lost during capacitation (Lopez et al. 1985; Wilson and Oliphant 1987). It is possible that these compounds block the recognition sites for the sperm proteins that bind to the zona pellucida. It has been suggested that the unmasking of these sites might be one of the effects of cholesterol depletion (Benoff 1993). The membrane potential of the sperm cell becomes more negative as potassium ions leave the sperm. This change in membrane potential may allow calcium channels to be opened and permit calcium to enter the sperm. Calcium and bicarbonate ions are critical in activating cAMP production and in facilitating the membrane fusion events of the acrosome reaction (Visconti et al. 1995; Arnoult et al. 1999). The influx of bicarbonate ions (and possibly other ions) alkalinizes the sperm, raising its pH. This is critical in the subsequent activation of calcium channels (Navarro et al. 2007). As a result of cAMP formation, protein phosphorylation occurs (Galantino-Homer et al. 1997; Arcelay et al. 2008). Once they are phosphorylated, some proteins migrate to the surface of the sperm head. One of these proteins is Izumo, which is critical in sperm-egg fusion (see Figure 7.30; Baker et al. 2010).
There may be an important connection between sperm translocation and capacitation. Smith (1998) and Suarez (1998) have documented that before entering the ampulla of the oviduct, the uncapacitated sperm bind actively to the membranes of the oviduct cells in the narrow passage (the isthmus) preceding it. This binding is temporary and appears to be broken when the sperm become capacitated. Moreover, the lifespan of the sperm is significantly lengthened by this binding. This restriction of sperm entry into the ampulla during capacitation, and the expansion of sperm lifespan, may have important consequences (Töpfer-Petersen et al. 2002; Gwathmey et al. 2003). The binding action may function as a block to polyspermy by preventing many sperm from reaching the egg at the same time (if the oviduct isthmus is excised in cows, a much higher rate of polyspermy results). In addition, slowing the rate of sperm capacitation and extending the active life of sperm may maximize the probability that sperm will still be available to meet the egg in the ampulla.