Artemisinins Target GABA(A) Receptor Signaling and Impair alpha Cell Identity

作者：Li, Jin; Casteels, Tamara; Frogne, Thomas; Ingvorsen, Camilla; Honore, Christian; Courtney, Monica; Huber, Kilian V. M.; Schmitner, Nicole; Kimmel, Robin A.; Romanov, Roman A.; Sturtzel, Caterina; Lardeau, Charles-Hugues; Klughammer, Johanna; Farlik, Matthias; Sdelci, Sara; Vieira, Andhira; Avolio, Fabio; Briand, Francois; Baburin, Igor; Majek, Peter; Pauler, Florian M.; Penz, Thomas; Stukalov, Alexey; Gridling, Manuela; Parapatics, Katja; Barbieux, Charlotte; Berishvili, Ekaterine

来源：Cell, 2017, 168(1-2): 86-+.

DOI：10.1016/j.cell.2016.11.010

• GLUCAGON-SECRETION
• ENDOCRINE PANCREAS
• SAMPLE PREPARATION
• BETA-CELLS
• GLUCOSE-INHIBITION
• SMALL MOLECULES
• INSULIN
• EXPRESSION
• CONVERSION
• GEPHYRIN

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.

• 出版日期2017-1-12
• 单位河北医科大学