: Humans and most other vertebrates have duplex retinas, in which nighttime vision is initiated by rod photoreceptor cells, and daytime vision by the less numerous cone cells. While the molecular mechanism underlying the responses of rods to light - the rod """"""""G protein-coupled receptor (GPCR) phototransduction cascade"""""""" - is now largely understood, and cones are known to have a related mechanism, relatively little is known about the unique features that allow cones to function so effectively under daylight conditions when supersensitive rods are in saturation and cannot signal. This research will use molecular biological manipulations in two vertebrate species, the amphibian, Xenopus laevis, and the mouse, to test hypotheses about the cellular and molecular mechanisms that allow cones to function so effectively in daylight, including the specific hypotheses that a distinct form of the Arrestin family of GPCR capping proteins, """"""""Arrestin 4,"""""""" and a relatively higher concentration of the transducin-GTPase activating factor, RGS9-GbetaL, allow cones to inactivate their GPCR cascade much faster than rods. Cones are also known to recover from intense light exposures much faster than rods. This research will investigate the dark adaptation of rods and cones of mice after exposure to strong light stimuli that """"""""bleach"""""""" a substantial fraction of their visual pigments, testing hypotheses about the roles of several key enzymatic steps in the """"""""retinoid cycle"""""""" in determining the distinct time courses of rod and cone dark adaptation, including the roles of the ABCR retinoid transporter, the cellular all-trans retinal dehydrogenase, and the retinal pigment epithelium dioxygenase homologue, RPE65. The research will impact on visual health as follows. First, it will provide a deeper understanding of the molecular mechanisms of cone or daytime vision, which are essential to normal human vision, but relatively poorly understood at the molecular level. Second, since the Xenopus retina possesses excellent cone function, it will develop this laboratory species as a relatively inexpensive preparation for the investigation of genetic eye disease affecting cone function. Third, it will expand on previous successes of this laboratory in characterizing cone function in the mouse, developing noninvasive electroretinographic methods and analyses of cone function directly applicable to human patients. Fourth, the investigations of dark adaptation in mice are expected to lead to a refined analysis of human dark adaptation, and the development of a quantitative model linking GPCR cascade inactivation and rod and cone pigment regeneration with the time course of dark adaptation.
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