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Cell. 2017 Jan 12;168(1-2):86-100.e15. doi: 10.1016/j.cell.2016.11.010. Epub 2016 Dec 1.

Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
2
Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
3
Université Côte d'Azur, INSERM, CNRS, iBV, 06108 Nice, France.
4
Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria.
5
Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
6
Children's Cancer Research Institute, Innovative Cancer Models, Zimmermannplatz 10, 1090 Vienna, Austria.
7
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria; Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria.
8
Physiogenex S.A.S., Prologue Biotech, 516, rue Pierre et Marie Curie, 31670 Labege, France.
9
Institute of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
10
Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland.
11
Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland; Institute of Medical Research, Ilia State University, Tbilisi 0162, Georgia.
12
Core Facility Flow Cytometry and Department of Surgery, Research Laboratories, Medical University of Vienna, 1090 Vienna, Austria.
13
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria; Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; Max Planck Institute for Informatics, 66123 Saarbrücken, Germany.
14
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria; Center for Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
15
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria; Christian Doppler Laboratory for Chemical Epigenetics and Antiinfectives, CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, 1090 Vienna, Austria. Electronic address: skubicek@cemm.oeaw.ac.at.

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:

ARX translocation; GABA-receptor signaling; artemisinins; chemical biology; diabetes; gephyrin; insulin secretion; pancreatic endocrine transdifferentiation; regenerative medicine; β cell

PMID:
27916275
PMCID:
PMC5236063
DOI:
10.1016/j.cell.2016.11.010
[Indexed for MEDLINE]
Free PMC Article

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