Sperm Motility Is Dependent on a Unique Isoform of the Na,K-ATPase

Woo, Alison L.; James, Paul F.; Lingrel, Jerry B.

doi:10.1074/jbc.m002323200

Cited by 144 publications

(183 citation statements)

References 41 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…The α4 polypeptide is the Na,K-ATPase isoform that is least abundantly expressed across the body. It has been found in male germ cells of the testis, where it predominates in the sperm flagellum [8,9]. The α4 isoform has particular affinities for Na + , K + and ATP [10,11] and is important for maintaining membrane potential, pH and the intracellular Na + and Ca +2 levels of sperm [12].…”

Section: Introductionmentioning

confidence: 99%

“…The α4 isoform has particular affinities for Na + , K + and ATP [10,11] and is important for maintaining membrane potential, pH and the intracellular Na + and Ca +2 levels of sperm [12]. Moreover, the α4 polypeptide plays a primary role in sperm motility [8,13,14] and it is fundamental for sperm fertility since knockout mice in which the α4 isoform has been deleted are completely sterile [15]. While original studies with specific antibodies identified α4 in testis male germ cells [8,10]; more recently, a work based on RT-PCR analysis, reported the presence of Na,K-ATPase α4 mRNA in Sertoli cells, suggesting that α4 expression may not be solely confined to male germ cells, but could also extend to somatic cells [16].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Green fluorescence protein driven by the Na,K-ATPase α4 isoform promoter is expressed only in male germ cells of mouse testis

McDermott

Sánchez

Chennathukuzhi

et al. 2012

J Assist Reprod Genet

View full text Add to dashboard Cite

Purpose Expression of the Na,K-ATPase α4 isoform is required for sperm motility and fertility and is controlled by the Atp1a4 promoter. Here, we have investigated the specific tissue, cell type and developmental regulation of expression mediated by the Atp1a4 promoter. Methods We have inserted the green fluorescent protein (GFP), downstream of the endogenous Atp1a4 promoter, in place of the Na,K-ATPase α4 gene, and used it as a marker for α4 expression in mice (Atp1a4 null(GFP) mice). Results Replacement of α4 by GFP completely disrupted α4 expression and activity, produced sperm morphological and functional abnormalities, and caused infertility of Atp1a4 null (GFP) male mice. Immunoblot analysis of Atp1a4 null (GFP) mouse tissues showed GFP expression in testis. This particular expression pattern was found in adult, but not in mouse embryos or in 7, 18 day old mice. In agreement with expression of GFP, adult Atp1a4 null(GFP) mouse testis displayed the typical fluorescence of GFP. Immunocytochemistry of testis identified GFP in more differentiated male germ cells, but not in spermatogonia, Leydig or Sertoli cells. Further analysis, using immunoblot of fluorescently sorted testis cells with cell specific markers, detected GFP only in spermatocytes, spermatids and spermatozoa. While epididymis showed GFP expression, this was confined to the spermatozoa within the epididymal tubules.Conclusions Our results show that the Atp1a4 promoter drives GFP expression exclusively in male germ cells of the testis, where it restricts it to post-meiotic stages of spermatogenesis. These findings highlight the exquisite spatial and temporal control of expression exerted by the Atp1a4 promoter on Na, K-ATPase α4, which is particularly well suited to fulfill the special functions of spermatozoa.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Green fluorescence protein driven by the Na,K-ATPase α4 isoform promoter is expressed only in male germ cells of mouse testis

McDermott

Sánchez

Chennathukuzhi

et al. 2012

J Assist Reprod Genet

View full text Add to dashboard Cite

show abstract

“…The ␣3 isoform is limited essentially to neural tissues and vascular smooth muscle and in some animals, such as humans, it is also found in the heart. The ␣4 isoform is present only in testes and specifically in spermatagonia and mature sperm (3).…”

mentioning

confidence: 99%

The highly conserved cardiac glycoside binding site of Na,K-ATPase plays a role in blood pressure regulation

Dostanic-Larson

Huysse

Lorenz

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

173

182

View full text Add to dashboard Cite

The Na,K-ATPase contains a binding site for cardiac glycosides, such as ouabain, digoxin, and digitoxin, which is highly conserved among species ranging from Drosophila to humans. Although advantage has been taken of this site to treat congestive heart failure with drugs such as digoxin, it is unknown whether this site has a natural function in vivo. Here we show that this site plays an important role in the regulation of blood pressure, and it specifically mediates adrenocorticotropic hormone (ACTH)-induced hypertension in mice. We used genetically engineered mice in which the Na,K-ATPase ␣2 isoform, which is normally sensitive to cardiac glycosides, was made resistant to these compounds. Chronic administration of ACTH caused hypertension in WT mice but not in mice with an ouabain-resistant ␣2 isoform of Na,K-ATPase. This finding demonstrates that the cardiac glycoside binding site of the Na,K-ATPase plays an important role in blood pressure regulation, most likely by responding to a naturally occurring ligand. Because the ␣1 isoform is sensitive to cardiac glycosides in humans, we developed mice in which the naturally occurring ouabain-resistant ␣1 isoform was made ouabain-sensitive. Mice with the ouabainsensitive ''human-like'' ␣1 isoform and an ouabain-resistant ␣2 isoform developed ACTH-induced hypertension to greater extent than WT animals. This result indicates that the cardiac glycoside binding site of the ␣1 isoform can also mediate ACTH-induced hypertension. Taken together these results demonstrate that the cardiac glycoside binding site of the ␣ isoforms of the Na,K-ATPase have a physiological function and supports the hypothesis for a role of the endogenous cardiac glycosides. adrenocorticotropic hormone ͉ hypertension ͉ endogenous cardiac glycosides

show abstract

“…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).…”

mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%