2. Academic Validation
  3. A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function

A selective inhibitor of the sperm-specific potassium channel SLO3 impairs human sperm function

  • Proc Natl Acad Sci U S A. 2023 Jan 24;120(4):e2212338120. doi: 10.1073/pnas.2212338120.
Maximilian Lyon 1,  Ping Li 1,  Juan J Ferreira 1,  Roman M Lazarenko 2,  Sujay V Kharade 2,  Meghan Kramer 2,  Samantha J McClenahan 2,  Emily Days 3,  Joshua A Bauer 3,  Brittany D Spitznagel 4,  C David Weaver 4,  Aluet Borrego Alvarez 1,  Lis C Puga Molina 1,  Pascale Lybaert 1 5,  Saayli Khambekar 1,  Alicia Liu 1,  Craig W Lindsley 3 4,  Jerod Denton 2 3 4,  Celia M Santi 1
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63110.
  • 2 Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
  • 3 Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232.
  • 4 Department of Pharmacology, Vanderbilt University, Nashville, TN 37232.
  • 5 Laboratoire de recherche en Reproduction humaine, Université Libre de Bruxelles, Bruxelles 1050, Belgium.
PMID: 36649421 DOI: 10.1073/pnas.2212338120
Abstract

To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining the molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods and detecting causes of idiopathic male infertility. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K+) channel SLO3 [C. M. Santi et al., FEBS Lett. 584, 1041-1046 (2010)]. In human sperm, it has long been unclear whether hyperpolarization depends on SLO3 or the ubiquitous K+ channel SLO1 [N. Mannowetz, N. M. Naidoo, S. A. S. Choo, J. F. Smith, P. V. Lishko, Elife 2, e01009 (2013), C. Brenker et al., Elife 3, e01438 (2014), and S. A. Mansell, S. J. Publicover, C. L. R. Barratt, S. M. Wilson, Mol. Hum. Reprod. 20, 392-408 (2014)]. In this work, we identified the first selective inhibitor for human SLO3-VU0546110-and showed that it completely blocked heterologous SLO3 currents and endogenous K+ currents in human sperm. This compound also prevented sperm from hyperpolarizing and undergoing hyperactivated motility and induced acrosome reaction, which are necessary to fertilize an egg. We conclude that SLO3 is the sole K+ channel responsible for hyperpolarization and significantly contributes to the fertilizing ability of human sperm. Moreover, SLO3 is a good candidate for contraceptive development, and mutation of this gene is a possible cause of idiopathic male infertility.

Keywords

SLO3; capacitation; drug discovery; human sperm; ion channels.

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