Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins

  • Vikram Babu Kasaragod
  • Torben Johann Hausrat
  • Natascha Schaefer
  • Maximilian Kuhn
  • Nikolaj Riis Christensen
  • Ingrid Tessmer
  • Hans Michael Maric
  • Kenneth Lindegaard Madsen
  • Christoph Sotriffer
  • Carmen Villmann
  • Matthias Kneussel
  • Hermann Schindelin

Abstract

The frontline anti-malarial drug artemisinin and its derivatives have also been implicated in modulating multiple mammalian cellular pathways, including the recent identification of targeting γ-aminobutyric acid type A receptor (GABAAR) signaling in the pancreas. Their molecular mechanism of action, however, remains elusive. Here, we present crystal structures of gephyrin, the central organizer at inhibitory postsynapses, in complex with artesunate and artemether at 1.5-Å resolution. These artemisinins target the universal inhibitory neurotransmitter receptor-binding epitope of gephyrin, thus inhibiting critical interactions between gephyrin and glycine receptors (GlyRs) as well as GABAARs. Electrophysiological recordings reveal a significant inhibition of gephyrin-mediated neurotransmission by artemisinins. Furthermore, clustering analyses in primary neurons demonstrate a rapid inhibition and a time-dependent regulation of gephyrin and GABAAR cluster parameters. Our data not only provide a comprehensive model for artemisinin-mediated modulation of inhibitory neurotransmission but also establish artemisinins as potential lead compounds to pharmacologically interfere with this process.

Bibliographical data

Original languageEnglish
ISSN0896-6273
DOIs
Publication statusPublished - 20.02.2019
PubMed 30704910