Royal College Of Surgeons Retina Research Articles

LIGHT‐INDUCED REDUCTION IN CYCLIC GMP OF RETINAL PHOTORECEPTOR CELLS IN VIVO: ABNORMALITIES IN THE DEGENERATIVE DISEASES OF RCS RATS AND rd MICE1

Abstract— The effect of light on the content of cyclic GMP in degenerative retinae of Royal College of Surgeons (RCS) rats and rd mice was compared with that in control retinae during postnatal maturation. In vivo, the cyclic GMP content of retinae of control rats or mice is light‐dependent after photoreceptor outer segments develop. Mature retinae of control animals have high levels of cyclic GMP in the dark which are reduced 40–50% upon illumination. In the rd mouse disorder, a light‐induced reduction in cyclic GMP content is observed while the rod outer segments are morphologically intact. The rd photoreceptor cells possess a phosphodiesterase which, when stabilized by freeze‐drying, has a Km similar to that of control photoreceptors, and an apparent Vmax that is below normal. It is suggested that developing rd visual cells have an abnormality in cyclic GMP metabolism which results in the accumulation of cyclic GMP within the entire cell but which does not prevent the light‐mediated reduction of cyclic GMP in their outer segment organelles. In the RCS dystrophy, a light‐induced reduction in cyclic GMP content is observed also during the period when photoreceptor outer segments are present. The cyclic GMP content of dark‐ or light‐adapted RCS retinae is below that of the respective controls. Biochemical and morphological observations show that cyclic GMP levels increase in rd visual cells and that they are reduced in photoreceptor cells of RCS retina before the onset of visual cell degeneration. Until detailed knowledge of the role of cyclic GMP in the visual cells is known, it is suggested that high or low levels of cyclic GMP in rd and RCS photoreceptors, respectively, result from differences in the etiology or histopathology of the mouse and rat diseases.

Cyclic nucleotide phosphodiesterases in dystrophic rat retinas: Guanosine 3′,5′ cyclic monophosphate anomalies during photoreceptor cell degeneration

The kinetic characteristics and enzyme activities of cyclic nucleotide phosphodiesterase (PDE), using cyclic-AMP (cyclic-AMP-PDE) or cyclic-GMP (cyclic-GMP-PDE) as substrate, have been measured in developing retinas of control and Royal College of Surgeons (RCS) rats. The latter are afflicted with an inherited degeneration of the retinal photoreceptor cells. Two classes of cyclic-AMP-PDE are localized in the inner layers and one is in the photoreceptor layer of both control and RCS retinas. In RCS retina, the activity of the photoreceptor-specific cyclic-AMP-PDE surpasses that of the control retina during most of the period when rod outer segment debris accumulates, and falls below that of the control retina when the photoreceptor population is depleted. These data suggest that the accumulated debris has the capacity to hydrolyze cyclic-AMP. One class of cyclic-GMP-PDE is localized in the inner layers and one is in the photoreceptor layer of both control and RCS retinas. The kinetic characteristics of cyclic-GMP-PDE in the layers of the RCS retina are similar to those of control retina for the first 14 days of life but, during the period when debris accumulates, the cyclic-GMP-PDE of the inner layers is not demonstrable and that of the photoreceptor layers shows altered kinetics. Thereafter, the latter disappears due to the depletion of the photoreceptor population, and cyclic-GMP-PDE of the inner layers is again observable. The anomalous kinetics and activities of cyclic-GMP-PDE apparently result from the association of cyclic-GMP-PDE enzymes with a heat-denaturable, non-dialyzable material which is derived from the RCS photoreceptor cells and/or accumulated debris. The specificity of the material for cyclic-GMP-PDE suggests that cyclic-GMP metabolism may be altered, in situ, before the RCS photoreceptor cells degenerate.