Na,K-ATPase α4 isoform is essential for sperm fertility

Abstract

Regulation of ion balance in spermatozoa has been shown to be essential for sperm motility and fertility. Control of intracellular ion levels requires the function of distinct ion-transport mechanisms at the cell plasma membrane. Active Na + and K + exchange in sperm is under the control of the Na,K-ATPase. Two molecular variants of the catalytic subunit of the Na,K-ATPase, α1 and α4, coexist in sperm. These isoforms exhibit different biochemical properties; however, their function in sperm fertility is unknown. In this work, we show that Na,K-ATPase α4 is essential for sperm fertility. Knockout male mice lacking α4 are completely sterile and spermatozoa from these mice are unable of fertilizing eggs in vitro. Furthermore, α4 deletion results in severe reduction in sperm motility and hyperactivation typical of sperm capacitation. In addition, absence of α4 causes a characteristic bend in the sperm flagellum, indicative of abnormal sperm ion regulation. Accordingly, α4-null sperm present increased intracellular Na + and cell plasma membrane depolarization. These results are unique in demonstrating the absolute requirement of α4 for sperm fertility. Moreover, the inability of α1 to compensate for α4 suggests that α4 is the Na,K-ATPase-α isoform directly involved in sperm fertility. Our findings show α4 as an attractive target for male contraception and open the possibility for the potential use of this Na,K-ATPase isoform as a biomarker for male fertility.

A critical role of solute carrier 22a14 in sperm motility and male fertility in mice

“…Besides the hypotonic stress, inhibition or deletion of ion channels has been shown to induce the hairpin-like bending. For example, Na, K-ATPase α4-null sperm23 or SLO3-null sperm2425 show the characteristic hairpin-shape abnormality with impaired motility and male fertility. This abnormal tail bending is thought to be attributed to the cell swelling caused by water influx.…”

Advances in understanding the role of cardiac glycosides in control of sodium transport in renal tubules

“…The a2-subunit is expressed in skeletal muscle, smooth muscle, heart, brain, lung, and adipocytes , Blanco 2005, Bystriansky & Kaplan 2007, Lingrel 2010. The a3-subunit is expressed in neurons, ovaries, and adult human heart (Sweadner 1989, Kaplan 2002, Lingrel 2010, while the a4-subunit is expressed in sperm (Shamraj & Lingrel 1994, Woo et al 1999, Wagoner et al 2005, Sanchez et al 2006, Jimenez et al 2010, 2011a,b, 2012. The Na C /K C ATPase a1-subunit in rodents is the least sensitive to cardiotonic steroids, whereas the a2-, a3-, and a4-subunits are highly sensitive to cardiotonic steroids.…”

Subunit Isoform Selectivity in Assembly of Na,K-ATPase α-β Heterodimers

“…In contrast, other Na,K-ATPase subunit isoforms are expressed in a tissue-specific manner. The ␣ 2 isoform is expressed mainly in muscle and nervous system (1-3, 6, 7); the ␣ 3 isoform is expressed mainly in neurons (8,9), whereas the ␣ 4 isoform is found only in testis (10,11). The ␤ 2 isoform is expressed predominantly in brain and muscle (3,7), whereas the ␤ 3 isoform is mainly expressed in lung, testis, skeletal muscle, and liver (12,13).…”

“…In vivo human mutations in the ␣ 2 and ␣ 3 isoforms are associated with neurological diseases, familial hemiplegic migraine type 2, and rapid-onset dystonia-parkinsonism (16). The ␣ 4 isoform is required for sperm motility and fertility (10,11). The ␤ 1 subunit plays an important role in intercellular adhesion in epithelia (17,18), and the ␤ 2 subunit, or adhesion molecule on glia (AMOG), 2 is important for adhesion and migration of neurons on glia (19).…”