Na,K-ATPase alpha4 Isoform Is Critical for Sperm Motility and Fertility.

Abstract

Active exchange of Na+ and K+ across the sperm plasma membrane is under the control of the Na,K-ATPase, an integral membrane enzyme, composed of catalytic alpha and glycosylated α subunits. Two molecular variants of the alpha subunit, the ubiquitous α1 and the sperm specific alpha4 coexist in the male gamete. These isoforms exhibit different biochemical properties; however, their function in sperm fertility is unknown. Here, we show that genetic deletion of alpha4 in mice causes complete male infertility. Sperm from these mice are unable to fertilize zona intact and zona free eggs in vitro. Sperm null in the alpha4 isoform show abnormal oocyte binding. Deletion of alpha4 produces severe reduction in sperm total, progressive and in a series of critical parameters of sperm motility. Moreover, alpha4 null sperm shows drastic reduction in the hyperactivation typical of sperm capacitation. In addition, absence of alpha4 causes a characteristic bend in the sperm flagellum, indicative of abnormal sperm ion regulation. Also, sperm devoid of alpha4 presents other alterations, including depolarization of the cell plasma membrane and increase in intracellular Na+ levels. Overall, this demonstrates the absolute requirement of alpha4 for sperm fertility and the inability of the alpha1 isoform to compensate for alpha4. Our findings reveal alpha4 as an attractive biomarker for male fertility and a novel target for male contraception. [Supported by NIH grants HD043044 and HD055763]. (poster)