Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Jin Li; Tamara Casteels; Thomas Frogne; Camilla Ingvorsen; Christian Honore; Monica Courtney; Kilian V. M. Huber; Nicole Schmitner; Robin A. Kimmel; Roman A. Romanov; Caterina Sturtzel; Charles-Hugues Lardeau; Johanna Klughammer; Matthias Farlik; Sara Sdelci; Andhira Vieira; Fabio Avolio; Francois Briand; Igor Baburin; Peter Majek; Florian M. Pauler; Thomas Penz; Alexey Stukalov; Manuela Gridling; Katja Parapatics; Charlotte Barbieux; Ekaterine Berishvili; Andreas Spittler; Jacques Colinge; Keiryn L. Bennett; Steffen Hering; Thierry Sulpice; Christoph Bock; Martin Distel; Tibor Harkany; Dirk Meyer; Giulio Superti-Furga; Patrick Collombat; Jacob Hecksher-Sorensen; Stefan Kubicek

doi:10.1016/j.cell.2016.11.010

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Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

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Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Jin Li, Tamara Casteels, Thomas Frogne, Camilla Ingvorsen, Christian Honore, Monica Courtney, Kilian V. M. Huber, Nicole Schmitner, Robin A. Kimmel, Roman A. Romanov, …

Cell, Vol.168(1-2), pp.86-100.e15

12/01/2017

DOI: https://doi.org/10.1016/j.cell.2016.11.010

PMID: 27916275

Résumé

Biochemistry & Molecular Biology

Cell Biology

Life Sciences & Biomedicine

Science & Technology

Type 1 diabetes is characterized by the destruction of pancreatic beta cells, and generating new insulin-producing cells from other cell types is a major aim of regenerative medicine. One promising approach is transdifferentiation of developmentally related pancreatic cell types, including glucagon-producing a cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of a cells to functional beta-like cells. Here, we identify artemisinins as small molecules that functionally repress Arx by causing its translocation to the cytoplasm. We show that the protein gephyrin is the mammalian target of these antimalarial drugs and that the mechanism of action of these molecules depends on the enhancement of GABA(A) receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic b cell mass from alpha cells.

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Titre: Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity
Créateurs - sans rôle: Jin Li - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Tamara Casteels - Austrian Acad Sci Lazarettgasse, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria
Thomas Frogne - Univ Vienna, Inst Pharmacol & Toxicol, Althanstrasse 14, A-1090 Vienna, Austria
Camilla Ingvorsen - Austrian Acad Sci Lazarettgasse, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria
Christian Honore - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Monica Courtney - Austrian Acad Sci, CeMM Res Ctr Mol Med, Christian Doppler Lab Chem Epigenet & Antunfect, Lazarettgasse 14, A-1090 Vienna, Austria
Kilian V. M. Huber - Univ Geneva, CH-1211 Geneva, Switzerland
Nicole Schmitner - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Robin A. Kimmel - Austrian Acad Sci Lazarettgasse, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria
Roman A. Romanov - Univ Hosp Geneva, Dept Surg, Cell Isolat & Transplantat Ctr, CH-1211 Geneva, Switzerland
Caterina Sturtzel - Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark
Charles-Hugues Lardeau
Johanna Klughammer - Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark
Matthias Farlik - Physiogenex SAS, Prologue Biotech, Rue Pierre & Marie Curie, F-31670 Labege, France
Sara Sdelci - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Andhira Vieira - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Fabio Avolio - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Francois Briand - Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark
Igor Baburin - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Peter Majek - Univ Co dAzur, CNRS, INSERM, IBV, F-06108 Nice, France
Florian M. Pauler
Thomas Penz - Novo Nordisk AS, Novo Nordisk Pk, DK-2760 Malov, Denmark
Alexey Stukalov - Med Univ Vienna, Dept Lab Med, A-1090 Vienna, Austria
Manuela Gridling - Austrian Acad Sci Lazarettgasse, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria
Katja Parapatics - Max Planck Inst Informat, D-66123 Saarbrucken, Germany
Charlotte Barbieux - Ilia State Univ, Inst Med Res, Tbilisi 0162, Georgia
Ekaterine Berishvili - Med Univ Vienna, Core Facil Flow Cytometry & Dept Surg, Res Labs, A-1090 Vienna, Austria
Andreas Spittler - Leopold Franzens Univ Innsbruck, Mol Biol, Technikerstr 25, A-6020 Innsbruck, Austria
Jacques Colinge - Med Univ Vienna, Dept Mol Neurosci, Ctr Brain Res, A-1090 Vienna, Austria
Keiryn L. Bennett - Leopold Franzens Univ Innsbruck, Mol Biol, Technikerstr 25, A-6020 Innsbruck, Austria
Steffen Hering
Thierry Sulpice
Christoph Bock - Karolinska Inst, Dept Neuroscience, S-17177 Stockholm, Sweden
Martin Distel - Austrian Acad Sci Lazarettgasse, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria
Tibor Harkany - Med Univ Vienna, Dept Mol Neurosci, Ctr Brain Res, A-1090 Vienna, Austria
Dirk Meyer
Giulio Superti-Furga - Max Planck Inst Informat, D-66123 Saarbrucken, Germany
Patrick Collombat - Med Univ Vienna, Dept Mol Neurosci, Ctr Brain Res, A-1090 Vienna, Austria
Jacob Hecksher-Sorensen - Leopold Franzens Univ Innsbruck, Mol Biol, Technikerstr 25, A-6020 Innsbruck, Austria
Stefan Kubicek - CeMM Research Center for Molecular Medicine
Détails de publication: Cell, Vol.168(1-2), pp.86-100.e15
Éditeur: Elsevier
Nombre de pages: 30
Note de subvention: DOC Fellowship of the Austrian Academy of Sciences Max-Planck Society; Max Planck Society DRC20091217179 / FMR 31-2012-783; 1-RSC-2014-100-I-X; 3-SRA-2015-20-Q-R; 17-2011-258 / JDRF award ERC-2015-AdG-695136; StG-2011-281265 / European Research Council; European Research Council (ERC) FWF P25659-B19 / Austrian Science Fund; Austrian Science Fund (FWF) INSERM AVENIR program; Institut National de la Sante et de la Recherche Medicale (Inserm) National Foundation for Research, Technology, and Development INSERM; Institut National de la Sante et de la Recherche Medicale (Inserm) NovoNordisk Foundation; Novo Nordisk Foundation
Identifiants: 99140036509311
Unité académique: Institut de Recherche en Cancérologie de Montpellier - IRCM
Langue: English
Type de ressource: Journal article