CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE : An Early Defect in Inherited Retinal Degeneration of C3H Mice

Cyclic nucleotides have been implicated in the differentiation and function of the vertebrate retina. In the normal retina of DBA mice, the specific activity of cyclic-nucleotide phosphodiesterase (PDE), with cyclic-AMP as the substrate (cAMP-PDE), increases eightfold between the 6th and 20th postnatal day. Kinetic analysis of retinae from newborn mice reveals a PDE with a single Michaelis constant (K(m)) value for cyclic-AMP (low K(m)-PDE). After the 6th postnatal day, a second PDE with a high K(m) for cyclic-AMP (high K(m)-PDE) can be demonstrated. The appearance and increasing activity of the high K(m)-PDE coincides with the differentiation and growth of photoreceptor outer segments. Additionally, the high K(m)-PDE is shown by microchemical techniques to be concentrated in the photoreceptor cell layer and the low K(m)-PDE within the inner layers of the normal retina. In C3H mice afflicted with an inherited degeneration of the photoreceptor layer, the postnatal increase in the specific activity of cAMP-PDE is substantially lower than in the normal retina. The postnatal increase in the specific activity of cAMP-PDE in two regions of the brain of C3H mice is the same as in the normal strain. A deficiency in high K(m)-PDE activity in the C3H retina is evident on the 7th postnatal day, when the activity of low K(m)-PDE, photoreceptor morphology, and rhodopsin content of these retina are essentially normal. In the adult C3H retina, the PDE activity with cyclic-GMP and cyclic-UMP as substrates is significantly below that of the normal retina. These data indicate that an alteration in cyclic-AMP metabolism occurs before photoreceptor cell degeneration in the retinae of C3H mice.