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Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Li, Jin
Casteels, Tamara
Frogne, Thomas
Ingvorsen, Camilla
Honoré, Christian
Courtney, Monica
Huber, Kilian V M
Schmitner, Nicole
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Published in Cell. 2017, vol. 168, no. 1-2, p. 86-100.e15
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.
Keywords AnimalsArtemetherArtemisinins/administration & dosage/pharmacologyCarrier Proteins/metabolismCell Transdifferentiation/drug effectsCells, CulturedDiabetes Mellitus/drug therapyDiabetes Mellitus, Type 1/drug therapy/pathologyDisease Models, AnimalGene Expression ProfilingHomeodomain Proteins/metabolismHumansInsulin/genetics/metabolismIslets of Langerhans/drug effectsMembrane Proteins/metabolismMiceProtein Stability/drug effectsRatsReceptors, GABA-A/metabolismSignal TransductionSingle-Cell AnalysisTranscription Factors/metabolismZebrafishgamma-Aminobutyric Acid/metabolism
PMID: 27916275
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Research groups Création de tissus par bio-ingénieurie et régénération d'organes (1021)
La transplantation d'îlots de Langerhans (623)
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LI, Jin et al. Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity. In: Cell, 2017, vol. 168, n° 1-2, p. 86-100.e15. doi: 10.1016/j.cell.2016.11.010 https://archive-ouverte.unige.ch/unige:138363

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Deposited on : 2020-07-10

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