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.