Ritanserin, a potent serotonin 2A receptor antagonist, represses MEK/ERK signalling pathway to restore PAX6 production and function in aniridia-like cellular model
| Autor: | Johanna Zerbib, Daniel Aberdam, Edward Pichinuk, Elie Frank, Léa Zennaro, Keren Oved, Orly Dorot, Lauriane N. Roux, Dominique Bremond-Gignac |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
MAPK/ERK pathway
PAX6 Transcription Factor Biophysics Ritanserin Haploinsufficiency Limbus Corneae Models Biological Biochemistry Cell Line Cell Movement medicine Humans Receptor Serotonin 5-HT2A Aniridia Molecular Biology Cell Proliferation Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 business.industry Stem Cells Drug Repositioning Epithelium Corneal Cell migration Cell Biology medicine.disease eye diseases Hedgehog signaling pathway HEK293 Cells Gene Expression Regulation Eye development Cancer research Serotonin Antagonists sense organs PAX6 Ophthalmic Solutions business Signal Transduction medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 582:100-104 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2021.10.036 |
| Popis: | Aniridia is a panocular inherited rare eye disease linked to heterozygous mutations on the PAX6 gene, which fail to properly produce sufficient protein essential for normal eye development and function. Most of the patients suffer from aniridia-related keratopathy, a progressive opacification of the cornea. There is no effective treatment for this blinding disease. Here we screen for small compounds and identified Ritanserin, a serotonin 2A receptor antagonist, that can rescue PAX6 haploinsufficiency of mutant limbal cells, defective cell migration and PAX6-target gene expression. We further demonstrated that Ritanserin activates PAX6 production through the selective inactivation of the MEK/ERK signaling pathway. Our data strongly suggest that repurposing this therapeutic molecule could be effective in preventing or treating existing blindness by restoring corneal transparency. |
| Databáze: | OpenAIRE |
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