Artemisinins Target GABA A Receptor Signaling and Impair α Cell Identity
| Autor: | Sara Sdelci, Tibor Harkany, Keiryn L. Bennett, Kilian Huber, Patrick Collombat, Christian Honoré, Florian M. Pauler, Matthias Farlik, Ekaterine Berishvili, Monica Courtney, Igor Baburin, Stefan Kubicek, Nicole Schmitner, Jin Li, Steffen Hering, Peter Májek, Jacob Hecksher-Sørensen, Thierry Sulpice, Martin Distel, Robin A. Kimmel, Charles-Hugues Lardeau, Manuela Gridling, Johanna Klughammer, Camilla Ingvorsen, Alexey Stukalov, Christoph Bock, Andhira Vieira, François Briand, Giulio Superti-Furga, Roman A. Romanov, Thomas Frogne, Dirk Meyer, Caterina Sturtzel, Thomas Penz, Fabio Avolio, Katja Parapatics, Jacques Colinge, Andreas Spittler, Charlotte Barbieux, Tamara Casteels |
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| Přispěvatelé: | Harbin Engineering University (HRBEU), Research Center for Molecular Medicine of the Austrian Academy of Sciences [Vienna, Austria] (CeMM ), Austrian Academy of Sciences (OeAW), CeMM Research Center for Molecular Medicine [Vienna, Austria], Novo Nordisk A/S , Danemark, Novo Nordisk, Institut de Biologie Valrose (IBV), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institute for Research on Cancer and Aging, Nice (IRCAN), INSERM, U1081, CNRS UMR 7284, Nice, Innsbruck Medical University [Austria] (IMU), Leopold Franzens Universität Innsbruck - University of Innsbruck, Medizinische Universität Wien = Medical University of Vienna, Karolinska Institutet [Stockholm], Tumor Immunology [Vienna, Austria] (Children’s Cancer Research Institute), St. Anna Kinderkrebsforschung e.V. [Vienna, Austria], CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria, Physiological Chemistry, Biocenter, Am Hubland, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), IBM PSSC Montpellier - Innovation Lab., IBM PSSC Montpellier, Physiogenex, University of Geneva [Switzerland], Geneva University Hospital (HUG), Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Children’s Cancer Research Institute [Vienna, Austria], University of Vienna [Vienna], Cancer Center Karolinska [Karolinska Institutet] (CCK), Directors's Laboratory, Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark [Lyngby] (DTU) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
insulin secretion Artemisinins/administration & dosage/pharmacology β cell Carrier Proteins/metabolism Diabetes Mellitus/drug therapy Mice Single-cell analysis Insulin-Secreting Cells GABA-receptor signaling Insulin artemisinins gamma-Aminobutyric Acid/metabolism Cells Cultured Zebrafish gamma-Aminobutyric Acid pancreatic endocrine transdifferentiation ddc:617 biology diabetes Protein Stability Receptors GABA-A/metabolism Transdifferentiation Diabetes Mellitus Type 1/drug therapy/pathology 3. Good health Cell biology medicine.anatomical_structure Biochemistry ARX translocation Artemether MESH: Animals Disease models animal Insulin/Genetics Signal transduction Artemisinins/Pharmacology Single-Cell Analysis Signal Transduction Cell type regenerative medicine chemical biology [SDV.CAN]Life Sciences [q-bio]/Cancer Cell Transdifferentiation/drug effects Article General Biochemistry Genetics and Molecular Biology Diabetes Mellitus Experimental Islets of Langerhans 03 medical and health sciences Genetic model Protein Stability/drug effects Diabetes Mellitus medicine Homeodomain Proteins/metabolism Regeneration Animals Humans Transcription Factors/metabolism Transcription factor Homeodomain Proteins Insulin/genetics/metabolism Gephyrin Biochemistry Genetics and Molecular Biology(all) Gene Expression Profiling Pancreatic islets Membrane Proteins Islets of Langerhans/drug effects Receptors GABA-A gephyrin Rats Disease Models Animal Diabetes Mellitus Type 1 030104 developmental biology Cell Transdifferentiation biology.protein Membrane Proteins/metabolism Carrier Proteins Transcription Factors |
| Zdroj: | Cell Cell, Elsevier, 2017, 168 (1-2), pp.86-100.e15. ⟨10.1016/j.cell.2016.11.010⟩ Cell, Vol. 168, No 1-2 (2017) pp. 86-100.e15 |
| ISSN: | 0092-8674 1097-4172 |
| Popis: | Summary 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. Graphical Abstract Highlights • Artemisinins inhibit ARX function and impair α cell identity • Compounds act by stabilizing gephyrin, thus enhancing GABAA receptor signaling • Artemisinins increase β cell mass in zebrafish and rodent models • Functional and transcriptional data indicate a conserved phenotype in human islets The anti-malarial drug Artemisinin can drive the in vivo conversion of pancreatic α cells into functional β-like cells through enhanced GABA signaling and may have potential as a therapeutic for diabetes. |
| Databáze: | OpenAIRE |
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