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Artemisinins Target GABAReceptor Signaling and Impair α Cell Identity.

Cell | 2017

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 GABAreceptor 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.

Pubmed ID: 27916275 RIS Download

Mesh terms: Animals | Artemisinins | Carrier Proteins | Cell Transdifferentiation | Cells, Cultured | Diabetes Mellitus | Diabetes Mellitus, Type 1 | Disease Models, Animal | Gene Expression Profiling | Homeodomain Proteins | Humans | Insulin | Islets of Langerhans | Membrane Proteins | Mice | Protein Stability | Rats | Receptors, GABA-A | Signal Transduction | Single-Cell Analysis | Transcription Factors | Zebrafish | gamma-Aminobutyric Acid

Antibodies used in this publication

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This is a list of tools and resources that we have found mentioned in this publication.


Synaptic Systems (tool)

RRID:SCR_013612

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ATCC (tool)

RRID:SCR_001672

Global nonprofit biological resource center (BRC) and research organization that provides biological products, technical services and educational programs to private industry, government and academic organizations. Its mission is to acquire, authenticate, preserve, develop and distribute biological materials, information, technology, intellectual property and standards for the advancement and application of scientific knowledge. The primary purpose of ATCC is to use its resources and experience as a BRC to become the world leader in standard biological reference materials management, intellectual property resource management and translational research as applied to biomaterial development, standardization and certification. ATCC characterizes cell lines, bacteria, viruses, fungi and protozoa, as well as develops and evaluates assays and techniques for validating research resources and preserving and distributing biological materials to the public and private sector research communities.

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ProteoWizard (tool)

RRID:SCR_012056

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RRID:SCR_008426

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RRID:SCR_000004

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RRID:SCR_005275

Software package to comprehensively evaluate different aspects of RNA-seq experiments, such as sequence quality, GC bias, polymerase chain reaction bias, nucleotide composition bias, sequencing depth, strand specificity, coverage uniformity and read distribution over the genome structure. RSeQC takes both SAM and BAM files as input, which can be produced by most RNA-seq mapping tools as well as BED files, which are widely used for gene models.

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RefSeq (tool)

RRID:SCR_003496

Database that provides a comprehensive, integrated, non-redundant, well-annotated set of sequences, including genomic DNA, transcripts, and proteins. It provides a stable reference for genome annotation, gene identification and characterization, mutation and polymorphism analysis (especially RefSeqGene records), expression studies, and comparative analyses. Included are sequences from plasmids, organelles, viruses, archaea, bacteria, and eukaryotes. Each RefSeq is constructed wholly from sequence data submitted to the International Nucleotide Sequence Database Collaboration (INSDC). It is a unique resource because it provides a large, multi-species, curated sequence database representing separate but explicitly linked records from genomes to transcripts and translation products, as appropriate. Unlike the sequence redundancy found in the public sequence repositories that comprise the INSDC, (i.e., NCBI's GenBank, the European Nucleotide Archive, and the DNA Data Bank of Japan), the RefSeq collection aims to provide, for each included species, a complete set of non-redundant, extensively cross-linked, and richly annotated nucleic acid and protein records. It is recognized, however, that the coverage and finishing of public sequence data varies from organism to organism so intermediate genomic records are provided in some circumstances. The RefSeq collection is available without restriction and can be retrieved in several different ways, such as by searching or by available links in NCBI resources, including PubMed, Nucleotide, Protein, Gene, and Map Viewer, searching with a sequence via BLAST, and downloading from the RefSeq FTP site.

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QIAGEN (tool)

RRID:SCR_008539

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Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor 546 (antibody)

RRID:AB_2534016

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rabbit anti-sheep IgG-HRP (antibody)

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RRID:AB_10013483

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Anti-GABA A Receptor alpha 2 antibody (antibody)

RRID:AB_2714216

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RRID:AB_887719

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Donkey anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor 488 (antibody)

RRID:AB_2535792

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Anti-Actin antibody produced in rabbit (antibody)

RRID:AB_476693

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Goat anti-Guinea Pig IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor 488 (antibody)

RRID:AB_2534117

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Anti-GABA A Receptor beta 2,3 Chain, extracellular domain of the beta2 & beta3 subunits of the GABA A receptor, clone BD17 antibody (antibody)

RRID:AB_2109419

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Human ARX Affinity Purified Polyclonal Ab antibody (antibody)

RRID:AB_10973178

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Akt (pan) (C67E7) Rabbit mAb antibody (antibody)

RRID:AB_915783

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Polyclonal Guinea Pig Anti- Insulin antibody (antibody)

RRID:AB_2617169

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Gephyrin antibody (antibody)

RRID:AB_1209349

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anti Alpha-1B adrenergic receptor antibody (antibody)

RRID:AB_972551

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ImageJ (tool)

RRID:SCR_003070

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RRID:SCR_013035

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alphaTC1 Clone 6 (cell line)

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