A new sperm-specific Na+/H+ Exchanger required for sperm motility and fertility

It has long been speculated that intracellular pH is a critical regulator of both invertebrate and vertebrate sperm motility(1-3), and sodium-hydrogen exchange has been suggested as a mediator of such pH(i) regulation in various instances(4,5). Two sodium-hydrogen exchangers (NHE1 and NHE5) are expressed in spermatozoa(6). However, elimination of the NHE1 gene fails to cause infertility(7), 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.