Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins.

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.

journal_name

Neuron

journal_title

Neuron

authors

Kasaragod VB,Hausrat TJ,Schaefer N,Kuhn M,Christensen NR,Tessmer I,Maric HM,Madsen KL,Sotriffer C,Villmann C,Kneussel M,Schindelin H

doi

10.1016/j.neuron.2019.01.001

subject

Has Abstract

pub_date

2019-02-20 00:00:00

pages

673-689.e11

issue

4

eissn

0896-6273

issn

1097-4199

pii

S0896-6273(19)30002-9

journal_volume

101

pub_type

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