Howard Hughes Medical Institute, Department of Molecular Biology and Genetics, andDepartment of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Received January 21, 1992; Revised Manuscript Received March 3, 1992 iR-hodopsin is the light-absorbing proteinthat mediates dim light vision. It has been a source of fascination for biochemists ever since the incisive experiments of Wilhelm Kuhne dem-onstrated its photolability and regeneration (Kuhne, 1878). In 1894 Konig reported the coincidencebetween the absorption spectrum of human rhodopsin and the action spectrum of night vision (Konig, 1894), the first experiment to explain visual performance in terms of protein chemistry. In the 1930s Wald discovered that rhodopsin consists of two parts, an apoprotein, opsin, joined to a chromophore, retinal (Wald, 1935a, b; Figure 1). In 1958 the photoisomerization of retinal from 11-cis to all-trans was identified as the initiating event in visual exci-tation (Hubbard & Kropf, 1958); indeed, it is the only light-sensitive event in allof vision. How does photoisomerization of retinal lead to the production of a neural signal? Thirty years ago Wald proposed “if rhodopsin were... a proenzyme, activated by the action of light, then it might catalyze the formation of many molecules of product in return for the absorption of a single photon. This would consitute one stage of amplification. If the prouct of this catalysis were a second enzyme, prepared tocatalyze in turn a further reaction, that would constitute a second stage of amplification”(Wald, 1961). This remarkable insight was realized 20 years laterwith the discovery that photoexcited rhodopsin catalyzes the activation of a G-protein (transducin) which in turn activates a cyclic GMP phosphodiesterase (Wheeler & Bitensky, 1977; Leibman & Pugh, 1979; Fung & Stryer, 1980; Fung et al., 1981). The resulting decline in free intracellular cyclic GMP closes cyclic GMP-activated channels in the outer segment plasma membrane, leading to a membrane hyperpolarization (Fesenko et al., 1985; Haynes & Yau, 1985).