Abstract
It has long been speculated that intracellular pH is a critical regulator of both invertebrate and vertebrate sperm motility1,2,3, and sodium–hydrogen exchange has been suggested as a mediator of such pHi regulation in various instances4,5. Two sodium–hydrogen exchangers (NHE1 and NHE5) are expressed in spermatozoa6. However, elimination of the NHE1 gene fails to cause infertility7, suggesting that normal sperm function is maintained in NHE1-null animals. Here, we used a functionally unbiased signal peptide trap screen to identify a novel sperm-specific NHE. The NHE contains 14 predicted transmembrane segments, including a potential voltage sensor and a consensus cyclic nucleotide-binding motif. Testis histology, sperm numbers and morphology were normal, but NHE-null males were completely infertile with severely diminished sperm motility. The addition of ammonium chloride, which elevates intracellular pH, partially rescued the motility and fertility defects. Surprisingly, cyclic AMP analogues almost completely rescued the motility and infertility phenotypes. The existence of this new sperm NHE provides an attractive contraceptive target, given its cell-specific expression and absolute requirement for fertility.
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Acknowledgements
We thank E. Lummus for technical assistance, R.E. Hammer for production of the animal chimaeras, A. Carlson and D. Bobcock for help with pHi measurements, and J. Pouyssegur for assisting in the determination of NHE expression and activity in NHE-deficient cells. We also appreciate the use of the Molecular Pathology Core Laboratory and Molecular and Cellular Imaging Facility at the University of Texas Southwestern Medical Center. This work was supported by the Howard Hughes Medical Institute, the Cecil H. & Ida Green Center for Reproductive Biology Sciences and grant HD 36022 from the National Institutes of Health.
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Wang, D., King, S., Quill, T. et al. A new sperm-specific Na+/H+ Exchanger required for sperm motility and fertility. Nat Cell Biol 5, 1117–1122 (2003). https://doi.org/10.1038/ncb1072
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DOI: https://doi.org/10.1038/ncb1072
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