1. Comment on 'Identification of Novel G Protein–Coupled Receptor 143 Ligands as Pharmacologic Tools for Investigating X-Linked Ocular Albinism'
- Author
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Anke C. Schiedel, Prashiela Manga, and Elisabetta De Filippo
- Subjects
Ocular albinism ,0301 basic medicine ,Albinism ,Tyrosinase ,DNA Mutational Analysis ,Computational biology ,Pharmacology ,Melanocyte ,Biology ,Ligands ,03 medical and health sciences ,OA1 ,medicine ,Arrestin ,Humans ,Receptor ,Eye Proteins ,Letters to the Editor ,ocular albinism ,Cells, Cultured ,X-linked ocular albinism ,X-linked recessive inheritance ,Melanosome ,G protein-coupled receptor ,Membrane Glycoproteins ,Chemistry ,Pimozide ,Biochemistry and Molecular Biology ,Wild type ,Genetic Diseases, X-Linked ,Exons ,medicine.disease ,Albinism, Ocular ,Ethacridine ,3. Good health ,Cell biology ,Pedigree ,medicine.anatomical_structure ,030104 developmental biology ,Mutation ,Niclosamide ,RNA ,Identification (biology) ,GPR143 ligands ,G protein–coupled receptor 143 ,pharmacologic tools - Abstract
Purpose GPR143 regulates melanosome biogenesis and organelle size in pigment cells. The mechanisms underlying receptor function remain unclear. G protein-coupled receptors (GPCRs) are excellent pharmacologic targets; thus, we developed and applied a screening approach to identify potential GPR143 ligands and chemical modulators. Methods GPR143 interacts with β-arrestin; we therefore established a β-arrestin recruitment assay to screen for compounds that modulate activity. Because GPR143 is localized intracellularly, screening with the wild-type receptor would be restricted to agents absorbed by the cell. For the screen we used a mutant receptor, which shows similar basal activity as the wild type but traffics to the plasma membrane. We tested two compound libraries and investigated validated hits for their effects on melanocyte pigmentation. Results GPR143, which showed high constitutive activity in the β-arrestin assay, was inhibited by several compounds. The three validated inhibitors (pimozide, niclosamide, and ethacridine lactate) were assessed for impact on melanocytes. Pigmentation and expression of tyrosinase, a key melanogenic enzyme, were reduced by all compounds. Because GPR143 appears to be constitutively active, these compounds may turn off its activity. Conclusions X-linked ocular albinism type I, characterized by developmental eye defects, results from GPR143 mutations. Identifying pharmacologic agents that modulate GPR143 activity will contribute significantly to our understanding of its function and provide novel tools with which to study GPCRs in melanocytes and retinal pigment epithelium. Pimozide, one of three GPR143 inhibitors identified in this study, maybe be a good lead structure for development of more potent compounds and provide a platform for design of novel therapeutic agents.
- Published
- 2017