PUBLICATION
A screen of pharmacologically active compounds to identify modulators of the Adgrg6/Gpr126 signalling pathway in zebrafish embryos
- Authors
- Asad, A., Shahidan, N.O., de la Vega de León, A., Wiggin, G.R., Whitfield, T.T., Baxendale, S.
- ID
- ZDB-PUB-230703-34
- Date
- 2023
- Source
- Basic & Clinical Pharmacology & Toxicology 133(4): 364-377 (Journal)
- Registered Authors
- Asad, Anzar, Baxendale, Sarah, Whitfield, Tanya T.
- Keywords
- Adgrg6, Gpr126, LOPAC library, chemical screen, inner ear, myelination, zebrafish
- MeSH Terms
-
- Animals
- Receptors, G-Protein-Coupled*/genetics
- Receptors, G-Protein-Coupled*/metabolism
- Signal Transduction
- Zebrafish*/genetics
- Zebrafish*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- PubMed
- 37394692 Full text @ Basic Clin. Pharmacol. Toxicol.
Citation
Asad, A., Shahidan, N.O., de la Vega de León, A., Wiggin, G.R., Whitfield, T.T., Baxendale, S. (2023) A screen of pharmacologically active compounds to identify modulators of the Adgrg6/Gpr126 signalling pathway in zebrafish embryos. Basic & Clinical Pharmacology & Toxicology. 133(4):364-377.
Abstract
Adhesion G protein-coupled receptors are an under-represented class of GPCRs in drug discovery. We previously developed an in vivo drug screening pipeline to identify compounds with agonist activity for Adgrg6 (Gpr126), an adhesion GPCR required for myelination of the peripheral nervous system in vertebrates. The screening assay tests for rescue of an ear defect found in adgrg6tb233c-/- hypomorphic homozygous mutant zebrafish, using the expression of versican b (vcanb) mRNA as an easily identifiable phenotype. In the current study, we used the same assay to screen a commercially available library of 1280 diverse bioactive compounds (Sigma LOPAC). Comparison with published hits from two partially overlapping compound collections (Spectrum, Tocris) confirms that the screening assay is robust and reproducible. Using a modified counter screen for myelin basic protein (mbp) gene expression, we have identified 17 LOPAC compounds that can rescue both inner ear and myelination defects in adgrg6tb233c-/- hypomorphic mutants, three of which (ebastine, S-methylisothiourea hemisulfate, and thapsigargin) are new hits. A further 25 LOPAC hit compounds were effective at rescuing the otic vcanb expression but not mbp. Together, these and previously-identified hits provide a wealth of starting material for the development of novel and specific pharmacological modulators of Adgrg6 receptor activity.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping