2. Academic Validation
  3. Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity

  • Cell. 2017 Jan 12;168(1-2):86-100.e15. doi: 10.1016/j.cell.2016.11.010.
Jin Li 1,  Tamara Casteels 1,  Thomas Frogne 2,  Camilla Ingvorsen 2,  Christian Honoré 2,  Monica Courtney 3,  Kilian V M Huber 1,  Nicole Schmitner 4,  Robin A Kimmel 4,  Roman A Romanov 5,  Caterina Sturtzel 6,  Charles-Hugues Lardeau 7,  Johanna Klughammer 1,  Matthias Farlik 1,  Sara Sdelci 1,  Andhira Vieira 3,  Fabio Avolio 3,  François Briand 8,  Igor Baburin 9,  Peter Májek 1,  Florian M Pauler 1,  Thomas Penz 1,  Alexey Stukalov 1,  Manuela Gridling 1,  Katja Parapatics 1,  Charlotte Barbieux 10,  Ekaterine Berishvili 11,  Andreas Spittler 12,  Jacques Colinge 1,  Keiryn L Bennett 1,  Steffen Hering 9,  Thierry Sulpice 8,  Christoph Bock 13,  Martin Distel 6,  Tibor Harkany 5,  Dirk Meyer 4,  Giulio Superti-Furga 14,  Patrick Collombat 3,  Jacob Hecksher-Sørensen 2,  Stefan Kubicek 15
Affiliations

Affiliations

  • 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: [email protected].
PMID: 27916275 DOI: 10.1016/j.cell.2016.11.010
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.

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