Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin
Rhodopsin is the G protein-coupled receptor of rod photoreceptor cells that mediates vertebrate vision at low light intensities. Mutations in rhodopsin cause inherited retinal degenerative diseases such as retinitis pigmentosa. Several therapeutic strategies have attempted to address and counteract...
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MDPI AG
2021-05-01
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| author | Neda Razzaghi Pol Fernandez-Gonzalez Aina Mas-Sanchez Guillem Vila-Julià Juan Jesus Perez Pere Garriga |
| author_facet | Neda Razzaghi Pol Fernandez-Gonzalez Aina Mas-Sanchez Guillem Vila-Julià Juan Jesus Perez Pere Garriga |
| author_sort | Neda Razzaghi |
| collection | DOAJ |
| description | Rhodopsin is the G protein-coupled receptor of rod photoreceptor cells that mediates vertebrate vision at low light intensities. Mutations in rhodopsin cause inherited retinal degenerative diseases such as retinitis pigmentosa. Several therapeutic strategies have attempted to address and counteract the deleterious effect of rhodopsin mutations on the conformation and function of this photoreceptor protein, but none has been successful in efficiently preventing retinal degeneration in humans. These approaches include, among others, the use of small molecules, known as pharmacological chaperones, that bind to the receptor stabilizing its proper folded conformation. Valproic acid, in its sodium valproate form, has been used as an anticonvulsant in epileptic patients and in the treatment of several psychiatric disorders. More recently, this compound has been tested as a potential therapeutic agent for the treatment of retinal degeneration associated with retinitis pigmentosa caused by rhodopsin mutations. We now report on the effect of sodium valproate on the conformational stability of heterologously expressed wild-type rhodopsin and a rhodopsin mutant, I307N, which has been shown to be an appropriate model for studying retinal degeneration in mice. We found no sign of enhanced stability for the dark inactive conformation of the I307N mutant. Furthermore, the photoactivated conformation of the mutant appears to be destabilized by sodium valproate as indicated by a faster decay of its active conformation. Therefore, our results support a destabilizing effect of sodium valproate on rhodopsin I307N mutant associated with retinal degeneration. These findings, at the molecular level, agree with recent clinical studies reporting negative effects of sodium valproate on the visual function of retinitis pigmentosa patients. |
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| last_indexed | 2024-03-10T11:15:09Z |
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| spelling | doaj.art-62ee022c99b547fea591167445101a0c2023-11-21T20:27:03ZengMDPI AGMolecules1420-30492021-05-012610303210.3390/molecules26103032Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor RhodopsinNeda Razzaghi0Pol Fernandez-Gonzalez1Aina Mas-Sanchez2Guillem Vila-Julià3Juan Jesus Perez4Pere Garriga5Grup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech, Edifici Gaia, Rambla de Sant Nebridi 22, 08222 Terrassa, SpainGrup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech, Edifici Gaia, Rambla de Sant Nebridi 22, 08222 Terrassa, SpainGrup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech, Edifici Gaia, Rambla de Sant Nebridi 22, 08222 Terrassa, SpainGrup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech., Avinguda Diagonal, 647, 08028 Barcelona, SpainGrup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech., Avinguda Diagonal, 647, 08028 Barcelona, SpainGrup de Biotecnologia Molecular i Industrial, Centre de Biotecnologia Molecular, Departament d’Enginyeria Química, Universitat Politècnica de Catalunya-Barcelona Tech, Edifici Gaia, Rambla de Sant Nebridi 22, 08222 Terrassa, SpainRhodopsin is the G protein-coupled receptor of rod photoreceptor cells that mediates vertebrate vision at low light intensities. Mutations in rhodopsin cause inherited retinal degenerative diseases such as retinitis pigmentosa. Several therapeutic strategies have attempted to address and counteract the deleterious effect of rhodopsin mutations on the conformation and function of this photoreceptor protein, but none has been successful in efficiently preventing retinal degeneration in humans. These approaches include, among others, the use of small molecules, known as pharmacological chaperones, that bind to the receptor stabilizing its proper folded conformation. Valproic acid, in its sodium valproate form, has been used as an anticonvulsant in epileptic patients and in the treatment of several psychiatric disorders. More recently, this compound has been tested as a potential therapeutic agent for the treatment of retinal degeneration associated with retinitis pigmentosa caused by rhodopsin mutations. We now report on the effect of sodium valproate on the conformational stability of heterologously expressed wild-type rhodopsin and a rhodopsin mutant, I307N, which has been shown to be an appropriate model for studying retinal degeneration in mice. We found no sign of enhanced stability for the dark inactive conformation of the I307N mutant. Furthermore, the photoactivated conformation of the mutant appears to be destabilized by sodium valproate as indicated by a faster decay of its active conformation. Therefore, our results support a destabilizing effect of sodium valproate on rhodopsin I307N mutant associated with retinal degeneration. These findings, at the molecular level, agree with recent clinical studies reporting negative effects of sodium valproate on the visual function of retinitis pigmentosa patients.https://www.mdpi.com/1420-3049/26/10/3032rhodopsinG protein-coupled receptorsodium valproateretinitis pigmentosaconformational stability |
| spellingShingle | Neda Razzaghi Pol Fernandez-Gonzalez Aina Mas-Sanchez Guillem Vila-Julià Juan Jesus Perez Pere Garriga Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin Molecules rhodopsin G protein-coupled receptor sodium valproate retinitis pigmentosa conformational stability |
| title | Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin |
| title_full | Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin |
| title_fullStr | Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin |
| title_full_unstemmed | Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin |
| title_short | Effect of Sodium Valproate on the Conformational Stability of the Visual G Protein-Coupled Receptor Rhodopsin |
| title_sort | effect of sodium valproate on the conformational stability of the visual g protein coupled receptor rhodopsin |
| topic | rhodopsin G protein-coupled receptor sodium valproate retinitis pigmentosa conformational stability |
| url | https://www.mdpi.com/1420-3049/26/10/3032 |
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