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1.
Invest Ophthalmol Vis Sci ; 58(7): 3118-3126, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28632878

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 ß-arrestin; we therefore established a ß-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 ß-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.


Subject(s)
Albinism, Ocular/genetics , Eye Proteins/genetics , Genetic Diseases, X-Linked/genetics , Membrane Glycoproteins/genetics , Mutation , RNA/genetics , Albinism, Ocular/drug therapy , Albinism, Ocular/metabolism , Cells, Cultured , DNA Mutational Analysis , Ethacridine/pharmacology , Exons , Eye Proteins/antagonists & inhibitors , Eye Proteins/metabolism , Genetic Diseases, X-Linked/diet therapy , Genetic Diseases, X-Linked/metabolism , Humans , Ligands , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/metabolism , Niclosamide/pharmacology , Pedigree , Pimozide/pharmacology
3.
J Lipid Res ; 44(3): 560-6, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12562862

ABSTRACT

The object of this study was to investigate whether the levels of cardiolipin in cultured skin fibroblasts of patients with Barth syndrome (BTHS) can be restored by addition of linoleic acid to growth media. To this end, fibroblasts from controls and BTHS patients were grown in the presence or absence of linoleic acid. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry was used for quantitative and compositional analysis of cardiolipin. Incubation of cells from both BTHS and controls with different concentrations of linoleic acid led to a dose- and time-dependent increase of cardiolipin levels. The increased levels of cardiolipin in fibroblasts of BTHS patients after treatment with linoleic acid indicate that an increased amount of linoleic acid in the diet might be beneficial to BTHS patients.


Subject(s)
Cardiolipins/metabolism , Fibroblasts/drug effects , Fibroblasts/metabolism , Genetic Diseases, X-Linked/drug therapy , Linoleic Acid/pharmacology , Adolescent , Cells, Cultured , Child , Chromatography, High Pressure Liquid , Fibroblasts/pathology , Genetic Diseases, X-Linked/diet therapy , Humans , Infant , Linoleic Acid/therapeutic use , Phosphatidylglycerols/analysis , Spectrometry, Mass, Electrospray Ionization , Syndrome
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