1. Artemisinins Target GABA A Receptor Signaling and Impair α Cell Identity.
- Author
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Li J, Casteels T, Frogne T, Ingvorsen C, Honoré C, Courtney M, Huber KVM, Schmitner N, Kimmel RA, Romanov RA, Sturtzel C, Lardeau CH, Klughammer J, Farlik M, Sdelci S, Vieira A, Avolio F, Briand F, Baburin I, Májek P, Pauler FM, Penz T, Stukalov A, Gridling M, Parapatics K, Barbieux C, Berishvili E, Spittler A, Colinge J, Bennett KL, Hering S, Sulpice T, Bock C, Distel M, Harkany T, Meyer D, Superti-Furga G, Collombat P, Hecksher-Sørensen J, and Kubicek S
- Subjects
- Animals, Artemether, Artemisinins administration & dosage, Carrier Proteins metabolism, Cell Transdifferentiation drug effects, Cells, Cultured, Diabetes Mellitus drug therapy, Diabetes Mellitus, Type 1 pathology, Gene Expression Profiling, Homeodomain Proteins metabolism, Humans, Insulin genetics, Insulin metabolism, Islets of Langerhans drug effects, Membrane Proteins metabolism, Mice, Protein Stability drug effects, Rats, Single-Cell Analysis, Transcription Factors metabolism, Zebrafish, gamma-Aminobutyric Acid metabolism, Artemisinins pharmacology, Diabetes Mellitus, Type 1 drug therapy, Disease Models, Animal, Receptors, GABA-A metabolism, Signal Transduction
- 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 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 β cell mass from α cells., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2017
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