Na,K-ATPase alpha4 isoform in male germ cell physiology

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The Na,K-ATPase transporters comprise a group of relatively ubiquitous plasma membrane isozymes that use the energy from the hydrolysis of ATP to exchange cytoplasmic Na+ for extracellular K+. Isozyme diversity for the Na,K-ATPase results from the association of different molecular forms, or isoforms of two polypeptides, the catalytic α and glycosylated β subunits. Among these isoforms, the α4 polypeptide has the most restricted pattern of expression, and is selectively present in male germ cells. The α4 isoform exhibits several biochemical and functional characteristics that are highly unique and essential to sperm function. Importantly, α4 is necessary for normal motility of spermatozoa. Supporting its biological importance, we have shown that α4 undergoes significant developmental changes, and that its level of expression and activity increase dramatically after sperm meiosis. Once released, spermatozoa continue to undergo critical maturational changes that are essential for the cells to acquire their fertilizing ability. During this process, called capacitation, we found α4 activity to be up-regulated. While these results suggest an important role for α4 in sperm function, the precise mechanism(s) by which this protein contributes to sperm capacitation to regulate sperm fertility has yet to be fully defined. Our overall goal in this research is to determine the mechanism(s) by which the activity and ion transport function of the α4 isoform is regulated and the relevance of this event in sperm capacitation. Our central hypothesis is that the α4 isoform plays an important role in sperm physiology to maintain the ion gradients that control pH, membrane potential and motility changes that are hallmarks of sperm capacitation. Experiments are designed to identify the factors and mechanisms responsible for up-regulation of α4 activity, and to determine the contribution of these events to sperm capacitation. The results will have an important positive impact, because they will help to define the molecular basis of sperm capacitation and will contribute to future pharmacologic approaches that will target the α4 isoform to control male fertility.