Artemisinins Target GABA A Receptor Signaling and Impair α Cell Identity

Jin Li 1, 2 Tamara Casteels 3 Thomas Frogne 4 Camilla Ingvorsen 4 Christian Honoré 4 Monica Courtney 5, 6 Kilian V.M. Huber 2 Nicole Schmitner 7 Robin Kimmel 8 Roman Romanov 9, 10 Caterina Sturtzel 11 Charles-Hugues Lardeau 12 Johanna Klughammer 13 Matthias Farlik 12 Sara Sdelci 12 Andhira Vieira 5 Fabio Avolio 5 François Briand 14, 15 Igor Baburin 9 Peter Májek 9 Florian Pauler 2 Thomas Penz 12 Alexey Stukalov 3 Manuela Gridling 3 Katja Parapatics 3 Charlotte Barbieux 16 Ekaterine Berishvili 17 Andreas Spittler 9 Jacques Colinge 18 Keiryn Bennett 12 Steffen Hering 9 Thierry Sulpice 15 Christoph Bock 12 Martin Distel 19 Tibor Harkany 20, 21 Dirk Meyer 8 Giulio Superti-Furga 22, 2 Patrick Collombat 5 Jacob Hecksher-Sørensen 23 Stefan Kubicek 12
Abstract : Type 1 diabetes is characterized by the destruction of pancreatic β 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 α cells. In a genetic model, loss of the master regulatory transcription factor Arx is sufficient to induce the conversion of α cells to functional β-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 GABAA receptor signaling. Our results in zebrafish, rodents, and primary human pancreatic islets identify gephyrin as a druggable target for the regeneration of pancreatic β cell mass from α cells.
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https://hal.umontpellier.fr/hal-02284911
Contributeur : Nathalie Salvy-Cordoba <>
Soumis le : jeudi 12 septembre 2019 - 11:47:20
Dernière modification le : vendredi 13 septembre 2019 - 01:21:18

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Jin Li, Tamara Casteels, Thomas Frogne, Camilla Ingvorsen, Christian Honoré, et al.. Artemisinins Target GABA A Receptor Signaling and Impair α Cell Identity. Cell, Elsevier, 2017, 168 (1-2), pp.86-100.e15. ⟨10.1016/j.cell.2016.11.010⟩. ⟨hal-02284911⟩

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