The pumps that fuel a sperm's journey

Abstract

The sole purpose of a sperm cell is to carry genetic information from a male to a female egg. In order to accomplish this quest, the sperm cell must travel a long distance through a constantly changing environment. The success of this journey depends on membrane proteins that are uniquely expressed in sperm cells. One of these proteins is the α4 isoform of the sodium pump. This pump is optimized to cope with the ionic environment characteristic of the female reproductive tract, and its activity may be tightly coupled with secondary transporters that maintain cytoplasmic pH. Pharmacological inhibition of α4 is sufficient to inhibit sperm motility, and significant differences around the inhibitor-binding site compared with the ubiquitous α1 isoform, make α4 a feasible target in rational drug development.

The Structure and Function of the Na,K-ATPase Isoforms in Health and Disease

“…The primary sequences of the alpha isoforms are well conserved: alpha1, 2, and 3 are about 87% identical to each other and about 78% identical to the sperm-specific alpha4 (Shamraj and Lingrel, 1994). Between species, the identity percentages of alpha1, 2, and 3 are in the high nineties and for alpha4 in the low eighties (Clausen et al, 2011). Mapping the isoform differences on homology models of each alpha (Figure 3) shows that the variation is generally found at the surface of the protein, while the ion binding interior of the membrane domain and the linkers to the cytoplasmic domains are highly conserved.…”

“…The competitive spermatozoa evolution is evident from the high number of unique sperm cell proteins, particularly membrane proteins (Dorus et al, 2010). One of the sperm specific proteins is the alpha4 isoform of the sodium pump (Hlivko et al, 2006; McDermott et al, 2012), and the strong evolutionary pressure on sperm proteins is very apparent for alpha4, which is the most divergent of the Na,K-ATPase alpha subunits, both when compared with the other three alpha isoforms (Figure 3), and when compared between different species (Clausen et al, 2011). While alpha4 is considered a sperm specific Na,K-ATPase, a smaller protein from human skeletal muscle cross react with an alpha4 antisera (Sugiura et al, 2005), and mRNA that hybridize with alpha4 probes are present in human and mouse skeletal muscle (Keryanov and Gardner, 2002).…”

Pipeline for contraceptive development

“…Ouabain, a cardenolide analog, has higher affinity for the α4-subunit than other sodium pump subunits in both mice and humans. Targeted drug design, using the ouabain scaffold may yield derivatives with specificity for the α4-subunit and with selective regulation of sperm function (76, 77). …”

The α4 isoform of the Na+,K+‐ATPase is tuned for changing extracellular environments

“…The α4 isoform of the Na + ,K + ‐ATPase is a good example of a sperm membrane protein that has undergone rapid evolution. Compared with the three other Na + ,K + ‐ATPase isoforms (α1, 2 and 3), α4 is the most divergent in sequence , and it also has the most restricted expression profile, being found only in spermatozoa . Sperm cells from both human and rat express α1 and α4, and in mature sperm from rat, Na + ,K + ‐ATPase activity from α4 exceeds that of α1 by at least twofold .…”