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Artemisinins target GABA receptor signaling to induce alpha to beta cell transdifferentiation

GSE84714 Homo sapiens Expression profiling by high throughput sequencing 36 samples Submitted 2017/01/19 Platform GPL11154Platform GPL21290
Summary
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 alpha cells. In a genetic model, overexpression of the master regulatory transcription factor Pax4 or loss of its counterplayer Arx are sufficient to induce the conversion of alpha cells to functional beta-like cells. Here we identify artemisinins as small molecules that functionally repress Arx and induce beta-cell characteristics in alpha cells. We show that the protein gephyrin is the mammalian target of these antimalaria drugs. Finally, we demonstrate that gephyrin-mediated enhancement of GABAA receptor signaling is the mechanism of action of these molecules in pancreatic transdifferentiation. Our results indicate that gephyrin is a novel druggable target for the regeneration of pancreatic beta cell mass from alpha cells.
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Also filed as BioProject PRJNA330917 and SRA study SRP079357. Searching any of these in the dataset finder brings you back here.

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