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Neuron. 2019 Feb 20;101(4):673-689.e11. doi: 10.1016/j.neuron.2019.01.001. Epub 2019 Jan 28.

Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins.

Author information

1
Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany.
2
Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Falkenried 94, 20251 Hamburg, Germany.
3
Institute for Clinical Neurobiology, University of Würzburg, Versbacherstr. 5, 97078 Würzburg, Germany.
4
Institute of Pharmacy and Food Chemistry, Department of Chemistry and Pharmacy, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
5
Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
6
Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany; Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Biotechnology and Biophysics, Biocenter, University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
7
Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen, Denmark.
8
Institute of Structural Biology, Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany. Electronic address: hermann.schindelin@virchow.uni-wuerzburg.de.

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.

KEYWORDS:

GABA(A) receptors; anti-malarial drug; artemisinins; gephyrin; glycine receptors; inhibitory postsynapses; moonlighting protein; neurodevelopmental disorders; scaffolding protein; synaptic transmission

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