The retina converts light entering our eyes into an electrical signal through a biochemical process called phototransduction. This signal is then relayed to the visual cortex of the brain, where visual perception occurs. The visual system allows us to continually perceive light throughout our lives because it has the ability to regenerate proteins and the light-sensitive chromophore. The long-term objective of this research program is to elucidate the molecular steps involved in the events of phototransduction. This would greatly contribute to our understanding of the basis of retina pathologies and provide a foundation for rational approaches to their treatments. We propose to examine three fundamental elements of phototransduction through: (1) Visualization of rhodopsin and other components in the disk membranes using atomic force microscopy. The high-resolution structure of rhodopsin provides a detailed organization of the polypeptide chain in detergent-formed crystals. To understand how it works, however, studies in native membranes are essential. (2) Investigation of the regulation of guanylate cyclases by guanylate cyclase-activating proteins and other mechanisms that influence cGMP production. The key step of phototransduction has been initially characterized and regulatory mechanisms have been proposed. Further advancement is needed to understand how disruptions of these regulatory mechanisms lead to rod and cone dystrophies. (3) Application of pharmacological approaches to the rescue of the P23H opsin mutant, the most common mutation associated with retinitis pigmentosa (RP) in North America. Progress in the molecular understanding of phototransduction and the retinoid cycle has made it possible for rational design of rescue approaches to stabilize vision in several pathologies. This is a rare example in biology where basic understanding of fundamental processes at the structural level feeds back for potential pharmacological intervention with small chaperone-like molecules to refold mutated protein. ? ?
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