We will investigate the mechanisms that regulate recovery of sensitivity and responsiveness of cones and rods during and following exposure to bright light which allow these cells to respond to light over an immense intensity range. To do this we will make electrophysiological recordings of receptor current together with microspectrophotometric measurements of visual pigment and microfluorometric measurements of retinal to retinol reduction in solitary rods and cones. Measurements will be made in darkness before and following bleaching and following exogenous incorporation of retinal and its analogs. The following hypotheses will be tested: (1) Critical non-covalent interactions between prosthetic groups on retinal and opsin in different cone types regulate the decay of light-activated cone opsin (Meta II) by different mechanisms. These mechanisms assist to affect the rapid recovery of dark current and flash responses that occur during and following bright light exposure. We shall correlate effects on Meta II decay, retinal production, and receptor response recovery following bleaching and subsequent incorporation of a variety of native and analog retinoids into the visual pigment of intact cells to determine specific sites of interaction that on retinal that regulate response recovery. (2) Non-covalent occupancy of the cone binding site during pigment regeneration assists in the very rapid recovery of sensitivity that occurs during dark-adaptation. Such occupancy has the opposite effects in rods. We shall determine the time course of sensitivity recovery relative to that of pigment regeneration in cones and rods that have been exposed to retinoids that either simply occupy the opsin binding site or bind to opsin and subsequently form a visual pigment. We will use different retinoid analogs to determine the essential features that a retinoid must have to accelerate/impede sensitivity recovery during dark adaptation in these cells. (3) The reduction of all-trans retinal to all-trans retinol by NADPH, and subsequent retinol release from opsin limit the regeneration of visual pigment and recovery of visual sensitivity in vertebrate rods. We shall measure the recovery of sensitivity locally within outer segments of bleached rods before and following dialysis with solutions containing NADPH or its metabolic precursors (glucose-6 phosphate, ATP, etc.) to determine whether the reduction of retinal to retinol must occur to allow recovery of dark current and flash sensitivity, and to see if this response recovery can be limited by the supply of NADPH in the OS. Lay Summary: Recovery of sensitivity and responsiveness of rods and cones during and following bright light exposure is important for our ability to sense changes in our light environment. We propose physiological and biochemical experiments designed to increase our understanding of the cellular mechanisms that underlie this ability. Our ultimate goal is to understand retinal function under normal and disease related conditions.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Mariani, Andrew P
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Boston University
Schools of Medicine
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Sato, Shinya; Frederiksen, Rikard; Cornwall, M Carter et al. (2017) The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones. Vis Neurosci 34:E004
Yue, Wendy Wing Sze; Frederiksen, Rikard; Ren, Xiaozhi et al. (2017) Spontaneous activation of visual pigments in relation to openness/closedness of chromophore-binding pocket. Elife 6:
Frederiksen, Rikard; Nymark, Soile; Kolesnikov, Alexander V et al. (2016) Rhodopsin kinase and arrestin binding control the decay of photoactivated rhodopsin and dark adaptation of mouse rods. J Gen Physiol 148:1-11
Berry, Justin; Frederiksen, Rikard; Yao, Yun et al. (2016) Effect of Rhodopsin Phosphorylation on Dark Adaptation in Mouse Rods. J Neurosci 36:6973-87
Wilby, David; Toomey, Matthew B; Olsson, Peter et al. (2015) Optics of cone photoreceptors in the chicken (Gallus gallus domesticus). J R Soc Interface 12:20150591
Toomey, Matthew B; Collins, Aaron M; Frederiksen, Rikard et al. (2015) A complex carotenoid palette tunes avian colour vision. J R Soc Interface 12:20150563
Wang, Jin-shan; Nymark, Soile; Frederiksen, Rikard et al. (2014) Chromophore supply rate-limits mammalian photoreceptor dark adaptation. J Neurosci 34:11212-21
Frederiksen, Rikard; Boyer, Nicholas P; Nickle, Benjamin et al. (2012) Low aqueous solubility of 11-cis-retinal limits the rate of pigment formation and dark adaptation in salamander rods. J Gen Physiol 139:493-505
Nymark, S; Frederiksen, R; Woodruff, M L et al. (2012) Bleaching of mouse rods: microspectrophotometry and suction-electrode recording. J Physiol 590:2353-64
Koutalos, Yiannis; Cornwall, M Carter (2010) Microfluorometric measurement of the formation of all-trans-retinol in the outer segments of single isolated vertebrate photoreceptors. Methods Mol Biol 652:129-47

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