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Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins

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Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. / Kasaragod, Vikram Babu; Hausrat, Torben Johann; Schaefer, Natascha; Kuhn, Maximilian; Christensen, Nikolaj Riis; Tessmer, Ingrid; Maric, Hans Michael; Madsen, Kenneth Lindegaard; Sotriffer, Christoph; Villmann, Carmen; Kneussel, Matthias; Schindelin, Hermann.

In: NEURON, Vol. 101, No. 4, 20.02.2019, p. 673-689.e11.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Kasaragod, VB, Hausrat, TJ, Schaefer, N, Kuhn, M, Christensen, NR, Tessmer, I, Maric, HM, Madsen, KL, Sotriffer, C, Villmann, C, Kneussel, M & Schindelin, H 2019, 'Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins', NEURON, vol. 101, no. 4, pp. 673-689.e11. https://doi.org/10.1016/j.neuron.2019.01.001

APA

Kasaragod, V. B., Hausrat, T. J., Schaefer, N., Kuhn, M., Christensen, N. R., Tessmer, I., Maric, H. M., Madsen, K. L., Sotriffer, C., Villmann, C., Kneussel, M., & Schindelin, H. (2019). Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. NEURON, 101(4), 673-689.e11. https://doi.org/10.1016/j.neuron.2019.01.001

Vancouver

Kasaragod VB, Hausrat TJ, Schaefer N, Kuhn M, Christensen NR, Tessmer I et al. Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins. NEURON. 2019 Feb 20;101(4):673-689.e11. https://doi.org/10.1016/j.neuron.2019.01.001

Bibtex

@article{2d99d733c6a143cfb1aab78e2f175c3f,
title = "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-{\AA} 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 = "Journal Article",
author = "Kasaragod, {Vikram Babu} and Hausrat, {Torben Johann} and Natascha Schaefer and Maximilian Kuhn and Christensen, {Nikolaj Riis} and Ingrid Tessmer and Maric, {Hans Michael} and Madsen, {Kenneth Lindegaard} and Christoph Sotriffer and Carmen Villmann and Matthias Kneussel and Hermann Schindelin",
note = "Copyright {\textcopyright} 2019 Elsevier Inc. All rights reserved.",
year = "2019",
month = feb,
day = "20",
doi = "10.1016/j.neuron.2019.01.001",
language = "English",
volume = "101",
pages = "673--689.e11",
journal = "NEURON",
issn = "0896-6273",
publisher = "Cell Press",
number = "4",

}

RIS

TY - JOUR

T1 - Elucidating the Molecular Basis for Inhibitory Neurotransmission Regulation by Artemisinins

AU - Kasaragod, Vikram Babu

AU - Hausrat, Torben Johann

AU - Schaefer, Natascha

AU - Kuhn, Maximilian

AU - Christensen, Nikolaj Riis

AU - Tessmer, Ingrid

AU - Maric, Hans Michael

AU - Madsen, Kenneth Lindegaard

AU - Sotriffer, Christoph

AU - Villmann, Carmen

AU - Kneussel, Matthias

AU - Schindelin, Hermann

N1 - Copyright © 2019 Elsevier Inc. All rights reserved.

PY - 2019/2/20

Y1 - 2019/2/20

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.neuron.2019.01.001

DO - 10.1016/j.neuron.2019.01.001

M3 - SCORING: Journal article

C2 - 30704910

VL - 101

SP - 673-689.e11

JO - NEURON

JF - NEURON

SN - 0896-6273

IS - 4

ER -