Abstract
Phototransduction is initiated when the absorption of light converts the 11-cis-retinal chromophore to its all-trans configuration in both rod and cone vertebrate photoreceptors. To sustain vision, 11-cis-retinal is continuously regenerated from its all-trans conformation through a series of enzymatic steps comprising the "visual or retinoid" cycle. Abnormalities in this cycle can compromise vision because of the diminished supply of 11-cis-retinal and the accumulation of toxic, constitutively active opsin. As shown previously for rod cells, attenuation of constitutively active opsin can be achieved with the unbleachable analogue, 11-cis-6-membered ring (11-cis-6mr)-retinal, which has therapeutic effects against certain degenerative retinal diseases. However, to discern the molecular mechanisms responsible for this action, pigment regeneration with this locked retinal analogue requires delineation also in cone cells. Here, we compared the regenerative properties of rod and green cone opsins with 11-cis-6mr-retinal and demonstrated that this retinal analogue could regenerate rod pigment but not green cone pigment. Based on structural modeling suggesting that Pro-205 in green cone opsin could prevent entry and binding of 11-cis-6mr-retinal, we initially mutated this residue to Ile, the corresponding residue in rhodopsin. However, this substitution did not enable green cone opsin to regenerate with 11-cis-6mr-retinal. Interestingly, deletion of 16 N-terminal amino acids in green cone opsin partially restored the binding of 11-cis-6mr-retinal. These results and our structural modeling indicate that a more complex binding pathway determines the regeneration of mammalian green cone opsin with chromophore analogues such as 11-cis-6mr-retinal.
Highlights
Phototransduction is initiated when the absorption of light converts the 11-cis-retinal chromophore to its all-trans configuration in both rod and cone vertebrate photoreceptors
Rho and cone opsins belong to the same family of G protein-coupled receptors (GPCRs)3 and use 11-cis-retinal as the chromophore covalently attached to a Lys residue side chain in the apoprotein via a Schiff base
A protonated Schiff base bond is a common feature of all vertebrate visual pigments, their sensitivity across the light spectrum differs, which is attributed to specific interactions between the chromophore and neighboring amino acids in the binding pocket [3]
Summary
The visual signaling cascade starts in photoreceptor cells with the absorption of a photon by a visual pigment, which leads to electrical responses deciphered in the brain. A protonated Schiff base bond is a common feature of all vertebrate visual pigments, their sensitivity across the light spectrum differs, which is attributed to specific interactions between the chromophore and neighboring amino acids in the binding pocket [3]. Rod and cone photoreceptor cell outer segments and the retinal pigment epithelium regulate a visual cycle to ensure a constant supply of newly regenerated 11-cis-retinal [11]. 11-cis-6mr-retinal has been proposed as an effective candidate for such therapy By using this retinal, toxic photoproducts could be curtailed without eliminating phototransduction in its entirety, because Rho regenerated with 11-cis-6mr-retinal exhibits residual light-dependent activity in vitro and in vivo [24]. Transition of Rho regenerated with this locked retinal to the active Meta II-like state is achieved most likely due to an isomerization around another C13ϭC14 double bond [25, 27]. We found that 11-cis-6mr-retinal was unable to regenerate green cone opsin, and we discerned that the N-terminal sequence of the opsin contributes to this property
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