A novel cross-species inhibitor to study the function of CatSper Ca2+ channels in sperm

Research output: Contribution to journalArticlepeer-review

Authors

  • Andreas Rennhack
  • Christian Schiffer
  • Christoph Brenker
  • Dmitry Fridman
  • Elis Nitao
  • Yi-Min Cheng
  • Lars Tamburrino
  • Melanie Balbach
  • Gabriel Stölting
  • Thomas K. Berger
  • Michelina Kierzek
  • Luis Alvarez
  • Dagmar Wachten
  • Xu-Hui Zeng
  • Elisabetta Baldi
  • U. Benjamin Kaupp
  • Timo Strünker

Colleges, School and Institutes

External organisations

  • Department Molecular Sensory Systems, Center of Advanced European Studies and Research (CAESAR),
  • Centre of Reproductive Medicine and Andrology, University Hospital Münster
  • Institute of Life Science and School of Life Science, Nanchang University
  • Department of Experimental and Clinical Medicine, Center of Excellence DeNothe, University of Florence
  • Institute of Complex Systems
  • Max-Planck Research Group, Molecular Physiology, Center of Advanced European Studies and Research (CAESAR)
  • Institute of Innate Immunity, University Hospital, University of Bonn

Abstract

Background and Purpose: Sperm from many species share the sperm-specific Ca2+ channel CatSper (cation channel of sperm) that controls the intracellular Ca2+ concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling CatSper activity and the role of the channel during fertilization differ among species. However, a lack of suitable pharmacological tools has hampered the elucidation of the function of CatSper. Known CatSper inhibitors exhibit considerable side effects and inhibit also Slo3, the K+ channel in mammalian sperm.


Experimental Approach: The drug RU1968 was reported to suppress Ca2+ signaling in human sperm by an unknown mechanism. We resynthesized the drug and revisited its mechanism of action in sperm form humans, mice, and sea urchins.


Key Results: We show by Ca2+ fluorimetry, single-cell Ca2+ imaging, electrophysiology, opto-chemistry, and motility analysis that RU1968 inhibits CatSper in sperm from invertebrates and mammals. The drug lacks toxic side effects in human sperm, does not affect mouse Slo3, and inhibits human Slo3 with about 15-fold lower potency than CatSper. Moreover, in human sperm, the inhibitor mimics CatSper dysfunction and suppresses motility responses evoked by progesterone, an oviductal steroid that activates CatSper. Finally, we show that the drug abolishes CatSper-mediated chemotactic navigation in sea urchin sperm.

Details

Original languageEnglish
JournalBritish Journal of Pharmacology
Publication statusPublished - 21 Apr 2018