Abstract
Rhodopsin (Rho) is a visual G protein-coupled receptor expressed in the rod photoreceptors of the eye, where it mediates transmission of a light signal into a cell and converts this signal into a nerve impulse. More than 100 mutations in Rho are linked to various ocular impairments, including retinitis pigmentosa (RP). Accordingly, much effort has been directed toward developing ligands that target Rho and improve its folding and stability. Natural compounds may provide another viable approach to such drug discovery efforts. The dietary polyphenol compounds, ubiquitously present in fruits and vegetables, have beneficial effects in several eye diseases. However, the underlying mechanism of their activity is not fully understood. In this study, we used a combination of computational methods, biochemical and biophysical approaches, including bioluminescence resonance energy transfer, and mammalian cell expression systems to clarify the effects of four common bioactive flavonoids (quercetin, myricetin, and their mono-glycosylated forms quercetin-3-rhamnoside and myricetrin) on rod opsin stability, function, and membrane organization. We observed that by directly interacting with ligand-free opsin, flavonoids modulate its conformation, thereby causing faster entry of the retinal chromophore into its binding pocket. Moreover, flavonoids significantly increased opsin stability, most likely by introducing structural rigidity and promoting receptor self-association within the biological membranes. Of note, the binding of flavonoids to an RP-linked P23H opsin variant partially restored its normal cellular trafficking. Together, our results suggest that flavonoids could be utilized as lead compounds in the development of effective nonretinoid therapeutics for managing RP-related retinopathies.
Highlights
Rhodopsin (Rho) is a visual G protein– coupled receptor expressed in the rod photoreceptors of the eye, where it mediates transmission of a light signal into a cell and converts this signal into a nerve impulse
We used a combination of computational methods, biochemical and biophysical approaches, including bioluminescence resonance energy transfer, and mammalian cell expression systems to clarify the effects of four common bioactive flavonoids on rod opsin stability, function, and membrane organization
The crystal structure of bovine rod opsin (PDB code 3CAP [33]) was used as a template to identify the possible interaction sites of quercetin, myricetin, quercetin-3-rhamnoside, and myricetrin with the ligand-free opsin, and the pocket analysis was performed with the CASTp software (Fig. 1a)
Summary
Discovering new allosteric modulators of GPCRs is another promising avenue to explore for achieving higher drug-receptor specificity. Several such modulators are already Food and Drug Administration–approved medications (6 –8). The effect of flavonoids on the stability, function, and oligomeric membrane organization of Rho is not entirely clear. Here we describe studies of the effects of four common bioactive flavonoids, quercetin 2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen4-one and myricetin 3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-one and their mono-glycosylated forms [31, 32] on rod opsin stability, its function, and membranous supramolecular assembly in vitro and in living cells
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
