11-cis- and All-trans-Retinols Can Activate Rod Opsin: Rational Design of the Visual Cycle^†

Rhodopsin is the photosensitive pigment in the rod photoreceptor cell. Upon absorption of a photon, the covalently bound 11-cis-retinal isomerizes to the all-trans form, enabling rhodopsin to activate transducin, its G protein. All-trans-retinal is then released from the protein and reduced to all-trans-retinol. It is subsequently transported to the retinal pigment epithelium where it is converted to 11-cis-retinol and oxidized to 11-cis-retinal before it is transported back to the photoreceptor to regenerate rhodopsin and complete the visual cycle. In this study, we have measured the effects of all-trans- and 11-cis-retinals and -retinols on the opsin’s ability to activate transducin to ascertain their potentials for activating the signaling cascade. Only 11-cis-retinal acts as an inverse agonist to the opsin. All-trans-retinal, all-trans-retinol, and 11-cis-retinol are all agonists with all-trans-retinal being the most potent agonist and all-trans-retinol being the least potent. Taken as a whole, our study is consistent with the hypothesis that the steps in the visual cycle are optimized such that the rod can serve as a highly sensitive dim light receptor. All-trans-retinal is immediately reduced in the photoreceptor to prevent back reactions and to weaken its effectiveness as an agonist before it is transported out of the cell; oxidation of 11-cis-retinol occurs in the retinal pigment epithelium and not the rod photoreceptor cell because 11-cis-retinol can act as an agonist and activate the signaling cascade if it were to bind an opsin, effectively adapting the cell to light.