Elucidating the molecular basis for inhibitory neurotransmission regulation by artemisinins.

摘要: 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 pancreas. Their molecular mechanism action, however, remains elusive. Here, we present crystal structures gephyrin, central organizer at inhibitory postsynapses, complex with artesunate artemether 1.5-A resolution. These artemisinins target universal neurotransmitter receptor-binding epitope thus inhibiting critical interactions between gephyrin glycine receptors (GlyRs) as well GABAARs. Electrophysiological recordings reveal a significant inhibition gephyrin-mediated neurotransmission by artemisinins. Furthermore, clustering analyses primary neurons demonstrate rapid time-dependent regulation GABAAR cluster parameters. Our data not only provide comprehensive model for artemisinin-mediated modulation but establish potential lead compounds to pharmacologically interfere this process.