PUBLICATION

Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity.

Authors
Li, J., Casteels, T., Frogne, T., Ingvorsen, C., Honoré, C., Courtney, M., Huber, K.V., Schmitner, N., Kimmel, R.A., Romanov, R.A., Sturtzel, C., Lardeau, C.H., Klughammer, J., Farlik, M., Sdelci, S., Vieira, A., Avolio, F., Briand, F., Baburin, I., Májek, P., Pauler, F.M., Penz, T., Stukalov, A., Gridling, M., Parapatics, K., Barbieux, C., Berishvili, E., Spittler, A., Colinge, J., Bennett, K.L., Hering, S., Sulpice, T., Bock, C., Distel, M., Harkany, T., Meyer, D., Superti-Furga, G., Collombat, P., Hecksher-Sørensen, J., Kubicek, S.
ID
ZDB-PUB-161206-9
Date
2017
Source
Cell   168(1-2): 86-100.e15 (Journal)
Registered Authors
Distel, Martin, Kimmel, Robin, Meyer, Dirk, Schmitner, Nicole, Sturtzel, Caterina
Keywords
ARX translocation, GABA-receptor signaling, artemisinins, chemical biology, diabetes, gephyrin, insulin secretion, pancreatic endocrine transdifferentiation, regenerative medicine, β cell
MeSH Terms
  • Rats
  • Cell Transdifferentiation/drug effects
  • Protein Stability/drug effects
  • Carrier Proteins/metabolism
  • Cells, Cultured
  • Single-Cell Analysis
  • Animals
  • Transcription Factors/metabolism
  • Signal Transduction*
  • Receptors, GABA-A/metabolism*
  • Gene Expression Profiling
  • Artemisinins/administration & dosage
  • Artemisinins/pharmacology*
  • Islets of Langerhans/drug effects
  • Homeodomain Proteins/metabolism
  • Membrane Proteins/metabolism
  • Insulin/genetics
  • Insulin/metabolism
  • Diabetes Mellitus, Type 1/drug therapy*
  • Diabetes Mellitus, Type 1/pathology
  • Diabetes Mellitus/drug therapy
  • Mice
  • Humans
  • Disease Models, Animal*
  • gamma-Aminobutyric Acid/metabolism
  • Zebrafish
(all 26)
PubMed
27916275 Full text @ Cell
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.
Genes / Markers
Figures
Figure Gallery (2 images)
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Expression
Gene Antibody Fish Conditions Stage Qualifier Anatomy Assay Figure
Crimsonmitfab692/b692; ednrbab140/b140; ml32TgcontrolDays 7-13IHC
Crimsonmitfab692/b692; ednrbab140/b140; ml32Tgchemical ablation: pancreatic B cell, chemical treatment by environment: AP20187, chemical treatment by environment: artemetherDays 7-13IHC
Crimsonmitfab692/b692; ednrbab140/b140; ml32Tgchemical ablation: pancreatic B cell, chemical treatment by environment: AP20187Days 7-13IHC
GFPia1TgcontrolDay 4IFL
GFPia1Tgchemical treatment by environment: artemetherDay 4IFL
1 - 5 of 5
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Phenotype
Fish Conditions Stage Phenotype Figure
ia1Tgchemical treatment by environment: artemetherDay 4
mitfab692/b692; ednrbab140/b140; ml32Tgchemical ablation: pancreatic B cell, chemical treatment by environment: AP20187, chemical treatment by environment: artemetherDays 7-13
mitfab692/b692; ednrbab140/b140; ml32Tgchemical ablation: pancreatic B cell, chemical treatment by environment: AP20187, chemical treatment by environment: artemetherDays 7-13
mitfab692/b692; ednrbab140/b140; ml32Tgchemical ablation: pancreatic B cell, chemical treatment by environment: AP20187Days 7-13
mitfab692/b692; ednrbab140/b140; ml32Tgchemical ablation: pancreatic B cell, chemical treatment by environment: AP20187Days 7-13
ml10Tgchemical treatment by environment: artemetherDay 4
1 - 6 of 6
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
b140
    		Unknown
    b692
      		Point Mutation
      ia1TgTransgenic Insertion
        ml10TgTransgenic Insertion
          ml32TgTransgenic Insertion
            1 - 5 of 5
            Show
            Human Disease / Model
            Human Disease Fish Conditions Evidence
            diabetes mellitusTAS
            1 - 1 of 1
            Show
            Sequence Targeting Reagents
            Fish
            Antibodies
            Orthology
            Engineered Foreign Genes
            Marker Marker Type Name
            CrimsonEFGCrimson
            GFPEFGGFP
            mCherryEFGmCherry
            NTREFGNTR
            1 - 4 of 4
            Show
            Mapping
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            Citation
            Li, J., Casteels, T., Frogne, T., Ingvorsen, C., Honoré, C., Courtney, M., Huber, K.V., Schmitner, N., Kimmel, R.A., Romanov, R.A., Sturtzel, C., Lardeau, C.H., Klughammer, J., Farlik, M., Sdelci, S., Vieira, A., Avolio, F., Briand, F., Baburin, I., Májek, P., Pauler, F.M., Penz, T., Stukalov, A., Gridling, M., Parapatics, K., Barbieux, C., Berishvili, E., Spittler, A., Colinge, J., Bennett, K.L., Hering, S., Sulpice, T., Bock, C., Distel, M., Harkany, T., Meyer, D., Superti-Furga, G., Collombat, P., Hecksher-Sørensen, J., Kubicek, S. (2017) Artemisinins Target GABAA Receptor Signaling and Impair α Cell Identity.. Cell. 168(1-2):86-100.e15.