Rapid RGR-dependent visual pigment recycling is mediated by the RPE and specialized Müller glia

Retinylidene chromophore hydrolysis from mammalian visual and non-visual opsins

“…4 A ). Following photoisomerization, occurring on the timescale of femtoseconds, the hydrolysis of the bRGR photoproduct (bRGR∗) was recently determined to occur rapidly in native bovine RPE (bRPE) microsomal membranes with a half-life of around 7.5 s ( 15 ). For a better understanding of purified bRGR, a mammalian cell line was establishing in HEK293S GnTI - with stable expression of bRGR C-terminally tagged with 1D4 peptide for eventual immunopurification ( Fig.…”

“…Given the slow rate of dark adaptation, the classical visual cycle pathway of 11- cis -retinal production would be insufficient under daylight conditions to maintain high light sensitivity ( 12 , 13 ); thus, RGR provides a critical, alternative route using light to ultimately supply 11- cis -retinal ( 10 , 14 ). Recently, the rate of the hydrolytic release of 11- cis -retinal from RGR after photoisomerization of its all- trans -retinylidene adduct was found to be exceedingly fast at roughly 60-times the rate of hydrolytic release of all- trans agonist from photoactivated Rho ( 15 ). The structural features of RGR that modulate the hydrolysis of 11- cis -retinylidene photoproduct have yet to be discovered.…”

Cell-cell interaction in the pathogenesis of inherited retinal diseases

“…RGR lacks the motif to interact with G protein coupled receptor ( Fritze et al, 2003 ), consistent with their role as a photoisomerase instead of a signaling molecule to activate the phototransduction cascade. Recent studies show that RGR couples with RDH10 to convert all- trans retinol to 11- cis retinol in a light-dependent manner ( Morshedian et al, 2019 ; Tworak et al, 2023 ). Besides the role in cone-specific visual cycle, MG have also been reported to serve as optic fibers and direct the light to photoreceptors in guinea pigs ( Agte et al, 2011 ), yet whether this function preserves in human retina remains further investigation.…”

“…Under continuous light treatment, cone photoreceptors of Rgr −/− mice lose their sensitivity sooner compared to the wild type ones ( Morshedian et al, 2019 ). A recent study using an innovative cell type-specific gene reactivation approach confirms RGR is critical for cone photoreceptor function and such supporting function is contributed by both RPE and a subset of MG ( Tworak et al, 2023 ). This finding raises an interesting yet challenging question on the targeted cell types for therapies of RGR -RP.…”

“…Transduction of RPE and MG in treatments will impact not only the selection of AAV serotype and promoter but also the route of administration as intravitreal injection is more efficient than subretinal injection for transducing inner retinal cells. Such as in the case of RGR -RP, the RGR-dependent cone visual cycle is mediated by both RPE and a subtype of MG ( Tworak et al, 2023 ). It could be challenging to deliver viral vectors to both cell types efficiently.…”