Na,K-ATPase α4 isoform is essential for sperm fertility
Na,K-ATPase α4 isoform is essential for sperm fertility
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DOI：
10.1073/pnas.1016902108
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发表时间：
2011-01-11
影响因子：
11.1
通讯作者：
Blanco, Gustavo
中科院分区：
文献类型：
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作者：
Jimenez, Tamara;McDermott, Jeffrey P.;Blanco, Gustavo
精子中离子平衡的调节已被证明对精子活力和生育力至关重要。细胞内离子水平的控制需要细胞质膜上不同的离子转运机制的功能。精子中Na+和K+的交换受Na，K-ATP酶的控制。Na，K-ATP酶催化亚基的两种分子变体α 1和α 4在精子中共存。这些异构体表现出不同的生化特性;然而，它们在精子生育力中的功能尚不清楚。在这项工作中，我们表明，Na，K-ATPase α 4是必不可少的精子生育力。缺乏α 4基因敲除的雄性小鼠完全不育，这些小鼠的精子不能在体外受精卵。此外，α 4缺失导致精子活力严重降低和精子获能典型的超活化。此外，缺乏α 4导致精子鞭毛特征性弯曲，表明精子离子调节异常。因此，α 4缺失精子存在增加的细胞内Na+和细胞质膜去极化。这些结果在证明α 4对精子生育力的绝对需求方面是独一无二的。此外，α 1不能补偿α 4，这表明α 4是Na，K-ATP酶-a同工型，直接参与精子生育力。我们的研究结果显示α 4是男性避孕的一个有吸引力的靶点，并为这种Na，K-ATP酶亚型作为男性生育力的生物标志物的潜在用途提供了可能性。
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, alpha 1 and alpha 4, 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 alpha 4 is essential for sperm fertility. Knockout male mice lacking alpha 4 are completely sterile and spermatozoa from these mice are unable of fertilizing eggs in vitro. Furthermore, alpha 4 deletion results in severe reduction in sperm motility and hyper-activation typical of sperm capacitation. In addition, absence of alpha 4 causes a characteristic bend in the sperm flagellum, indicative of abnormal sperm ion regulation. Accordingly, alpha 4-null sperm present increased intracellular Na+ and cell plasma membrane depolarization. These results are unique in demonstrating the absolute requirement of alpha 4 for sperm fertility. Moreover, the inability of alpha 1 to compensate for alpha 4 suggests that alpha 4 is the Na, K-ATPase-a isoform directly involved in sperm fertility. Our findings show alpha 4 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.