title: Artemisinins Target GABAAReceptor Signaling and Impair α Cell Identity.
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 GABAAreceptor 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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Jin
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authors.lastname: Li
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Tamara
authors.initials: T
authors.lastname: Casteels
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Thomas
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authors.lastname: Frogne
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Ingvorsen
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Christian
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authors.lastname: Honoré
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, iBV, 06108 Nice, France.
authors.forename: Monica
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authors.lastname: Courtney
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Kilian V M
authors.initials: KVM
authors.lastname: Huber
authors.affiliation: Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitner
authors.affiliation: Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Kimmel
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Roman A
authors.initials: RA
authors.lastname: Romanov
authors.affiliation: Children's Cancer Research Institute, Innovative Cancer Models, Zimmermannplatz 10, 1090 Vienna, Austria.
authors.forename: Caterina
authors.initials: C
authors.lastname: Sturtzel
authors.affiliation: 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.
authors.forename: Charles-Hugues
authors.initials: CH
authors.lastname: Lardeau
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Johanna
authors.initials: J
authors.lastname: Klughammer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Farlik
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Sara
authors.initials: S
authors.lastname: Sdelci
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, iBV, 06108 Nice, France.
authors.forename: Andhira
authors.initials: A
authors.lastname: Vieira
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, iBV, 06108 Nice, France.
authors.forename: Fabio
authors.initials: F
authors.lastname: Avolio
authors.affiliation: Physiogenex S.A.S., Prologue Biotech, 516, rue Pierre et Marie Curie, 31670 Labege, France.
authors.forename: François
authors.initials: F
authors.lastname: Briand
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Igor
authors.initials: I
authors.lastname: Baburin
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Májek
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Florian M
authors.initials: FM
authors.lastname: Pauler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Penz
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Alexey
authors.initials: A
authors.lastname: Stukalov
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Manuela
authors.initials: M
authors.lastname: Gridling
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Katja
authors.initials: K
authors.lastname: Parapatics
authors.affiliation: Cell Isolation and Transplantation Center, Department of Surgery, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Barbieux
authors.affiliation: 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.
authors.forename: Ekaterine
authors.initials: E
authors.lastname: Berishvili
authors.affiliation: Core Facility Flow Cytometry and Department of Surgery, Research Laboratories, Medical University of Vienna, 1090 Vienna, Austria.
authors.forename: Andreas
authors.initials: A
authors.lastname: Spittler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences. Lazarettgasse 14, 1090 Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Institute of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.affiliation: Physiogenex S.A.S., Prologue Biotech, 516, rue Pierre et Marie Curie, 31670 Labege, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Sulpice
authors.affiliation: 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.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bock
authors.affiliation: Children's Cancer Research Institute, Innovative Cancer Models, Zimmermannplatz 10, 1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Distel
authors.affiliation: Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, 1090 Vienna, Austria; Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
authors.forename: Tibor
authors.initials: T
authors.lastname: Harkany
authors.affiliation: Institute of Molecular Biology, Leopold-Franzens-University Innsbruck, Technikerstr. 25, 6020 Innsbruck, Austria.
authors.forename: Dirk
authors.initials: D
authors.lastname: Meyer
authors.affiliation: 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.
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, iBV, 06108 Nice, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
authors.affiliation: Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hecksher-Sørensen
authors.affiliation: 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.
authors.forename: Stefan
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authors.lastname: Kubicek
mesh_terms: D000818:Animals; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D054338:Cell Transdifferentiation / Q000187:drug effects; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D055550:Protein Stability / Q000187:drug effects; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C469264:ARX protein, human; D037621:Artemisinins; D002352:Carrier Proteins; D018398:Homeodomain Proteins; D007328:Insulin; D008565:Membrane Proteins; D011963:Receptors, GABA-A; D014157:Transcription Factors; C073441:gephyrin; D005680:gamma-Aminobutyric Acid; D000077549:Artemether
keywords: ARX translocation; GABA-receptor signaling; artemisinins; chemical biology; diabetes; gephyrin; insulin secretion; pancreatic endocrine transdifferentiation; regenerative medicine; β cell