title: A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility.
abstract: It has long been speculated that intracellular pH is a critical regulator of both invertebrate and vertebrate sperm motility, and sodium-hydrogen exchange has been suggested as a mediator of such pH(i) regulation in various instances. Two sodium-hydrogen exchangers (NHE1 and NHE5) are expressed in spermatozoa. However, elimination of the NHE1 gene fails to cause infertility, 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.
authors.affiliation: Cecil H. & Ida Green Center for Reproductive Biology Sciences, Howard Hughes Medical Institute, and Department of Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9051, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Wang
authors.forename: Shelby M
authors.initials: SM
authors.lastname: King
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Quill
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Doolittle
authors.forename: David L
authors.initials: DL
authors.lastname: Garbers
mesh_terms: D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005260:Female; D005298:Fertility / Q000502:physiology*; D006863:Hydrogen-Ion Concentration / Q000187:drug effects; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D017923:Sodium-Hydrogen Exchangers / Q000235:genetics / Q000302:isolation & purification*; D013081:Sperm Motility / Q000502:physiology*; D013094:Spermatozoa / Q000378:metabolism*
chemical_list: D018076:DNA, Complementary; C480499:Slc9c1 protein, mouse; D017923:Sodium-Hydrogen Exchangers; D000643:Ammonium Chloride; D000242:Cyclic AMP