K. Palczewski

Rhodopsin—Advances and perspectives

Rhodopsin, the best-studied G-protein-coupled receptor (GPCR), was identified as the light-sensitive retinal photoreceptor molecule in the 1870s by Franz Boll (Baumann, 1977; Boll, 1877) and Willy Kuehne (Kuehne, 1878; Kuhne, 1977). Rhodopsin occupies center stage between two important physiological pathways, both carried out by functional modules (Hofmann, Spahn, Heinrich, & Heinemann, 2006): phototransduction as an archetype of a sensory transduction module and the retinoid cycle, in which the retinal chromophore is reisomerized in a long series of reactions. Phototransduction and the retinoid cycle play complementary roles in vertebrate vision. Early research focused on bleaching intermediates of rhodopsin and the identification of its chromophore, vitamin A aldehyde (retinal), by George Wald (Wald, 1968). Determination of the rhodopsin protein sequence (Hargrave, 1982; Ovchinnikov et al., 1982) and identification of its gene (Nathans & Hogness, 1983) in mammalian photoreceptor cells, followed by the cloning of genes encoding the cone and invertebrate (Drosophila melanogaster) photopigments (O’Tousa et al., 1985; Zuker, Cowman, & Rubin, 1985), represented major advances in rhodopsin research. Since 1990, rhodopsin research has accelerated dramatically. First, mutations in the human rhodopsin gene were found to be causative for autosomal dominant retinitis pigmentosa (Dryja et al., 1990). Today in excess of 100 mutations in the rhodopsin gene have been associated with dominant and recessive retinal dystrophies, as well as non-progressive stationary nightblindness. Second, the three-dimensional crystal structure of unbleached rhodopsin was determined, and represents the first such structure for any of the large family of heptaspanning membrane receptors (Palczewski et al., 2000). More recently, crystal structures of late photointermediates were reported (Salom et al., 2006). This structure is a first step towards an understanding of how changes on the cytoplasmic surface of rhodopsin enable the coupling to its cognate G protein, transducin. Moreover, several helices are likely involved in the oligomeric state of rhodopsin, including helices I and II, as derived from the crystallographic studies (Fig. 1), consistent with the previous modeling investigations.