convert it to 11-cis-retinal when illuminated. Therefore, RGR-opsins and retinochromes are thought to neither signal nor activate a phototransduction cascade but to work as photoisomerases to produce 11-cis-retinal for other opsins. This view is considered established in the opsin literature, even so it has not been shown, conclusively. In fact, the human MT2 melatonin receptor signals via a G-protein and has an NAxxY7.53 motif natively. If this motif is mutated to NPxxY7.53 (Ala7.50 → Pro7.50), the receptor cannot be activated, but can be rescued partially if the motif is mutated to NVxxY7.53 (Ala7.50 → Val7.50). Furthermore, when the motif is mutated to NAxxY7.53 (Pro7.50 → Ala7.50) in cattle rhodopsin, the mutant has 141% of wild type activity. This evidence shows that a GPCR does not need a standard NPxxY7.53 motif for signaling. Other residues and motifs Cys138 and Cys110 form a highly conserved disulfide bridge. Glu113 serves as the counterion, stabilizing the protonation of the Schiff linkage between Lys296 and the ligand retinal. The Glu134-Arg135-Tyr136 is another highly conserved motif, involved in the propagation of the transduction signal once a photon has been absorbed. Spectral tuning sites Certain amino acid residues, termed spectral tuning sites, have a strong effect on λmax values. Using site-directed mutagenesis, it is possible to selectively mutate these residues and investigate the resulting changes in light absorption properties of the opsin. It is important to differentiate spectral tuning sites, residues that affect the wavelength at which the opsin absorbs light, from functionally conserved sites, residues important for the proper functioning of the opsin. They are not mutually exclusive, but, for practical reasons, it is easier to investigate spectral tuning sites that do not affect opsin functionality. For a comprehensive review of spectral tuning sites see Yokoyama and Deeb. The impact of spectral tuning sites on λmax differs between different opsin groups and between opsin groups of different species. Opsins in the human eye, brain, and skin RPE, retinal pigment epithelium; ipRGC, intrinsically photosensitive retinal ganglion cells; OPL, outer plexiform layer; IPL, inner plexiform layer; GCL, ganglion cell layer Cuttlefish Cuttlefish and octopusses contain opsin in their skin as part of the chromophores. The opsin is part of the sensing network detecting the colour and shape of the cuttlefishes surroundings. Phylogeny Animal opsins (also known as type 2 opsins) are members of the seven-transmembrane-domain proteins of the G protein-coupled receptor (GPCR) superfamily. Animal opsins fall phylogenetically into