Involvement of Cyclic GMP Phosphodiesterase Activator in an Hereditary Retinal Degeneration

CYCLIC NUCLEOTIDES mediate many aspects of normal cellular metabolism; thus, degradation as well as synthesis of these intracellular mediators must be strictly regulated. Phosphodiesterase (PDE), the enzyme of cyclic nucleotide catabolism, is present in mammalian tissues in multiple forms, which differ in substrate specificity, kinetic characteristics and sub-cellular localisation. Moreover, a calcium-dependent protein activator (now called calmodulin) has been characterised that specifically activates at least one of the PDE types although other types of PDE are known to be activator independent. Thus, several mechanisms are present in vivo which allow strict control of PDE. A unique cyclic GMP-PDE is compartmentalised in the outer segments of retinal photoreceptor cells; its activity is low in the dark-adapted state but increases dramatically on light adaptation. The resulting drop in cyclic GMP content could serve as a chemical ‘signal’ in the normal visual process. However, despite much investigation of various cyclic nucleotide systems, no definitive information has been obtained which clearly links a disorder of cyclic nucleotide metabolism with a disease process elsewhere than in retina. We have recently presented preliminary evidence that an abnormality in cyclic GMP metabolism could be present in the retinas of Irish setter dogs with inherited rod–cone dysplasia that could lead to greatly increased cyclic GMP content, as had been reported in mice with inherited retinal degeneration. We now report that the basic defect in the disease seems to be a failure to switch PDE type and a concomitant decrease in protein activator concentration early in postnatal development, at the time of photoreceptor differentiation. Disciplines Eye Diseases | Ophthalmology | Veterinary Medicine This journal article is available at ScholarlyCommons: http://repository.upenn.edu/vet_papers/109