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Scientific article
Open access
English

Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Published inCell, vol. 168, no. 1-2, p. 86-100.e15
Publication date2017
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
  • Animals
  • Artemether
  • Artemisinins/administration & dosage/pharmacology
  • Carrier Proteins/metabolism
  • Cell Transdifferentiation/drug effects
  • Cells, Cultured
  • Diabetes Mellitus/drug therapy
  • Diabetes Mellitus, Type 1/drug therapy/pathology
  • Disease Models, Animal
  • Gene Expression Profiling
  • Homeodomain Proteins/metabolism
  • Humans
  • Insulin/genetics/metabolism
  • Islets of Langerhans/drug effects
  • Membrane Proteins/metabolism
  • Mice
  • Protein Stability/drug effects
  • Rats
  • Receptors, GABA-A/metabolism
  • Signal Transduction
  • Single-Cell Analysis
  • Transcription Factors/metabolism
  • Zebrafish
  • gamma-Aminobutyric Acid/metabolism
Citation (ISO format)
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
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Article (Published version)
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Identifiers
ISSN of the journal0092-8674
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