Involvement of cyclic GMP phosphodiesterase activator in an hereditary retinal degeneration.

Abstract

CYCLIC NUCLEOTIDES mediate many aspects of normal cellular metabolism1; 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 localisation2. Moreover, a calcium-dependent protein activator (now called calmodulin) has been characterised that specifically activates at least one of the PDE types3,4 although other types of PDE are known to be activator independent5,6. 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 cells7–10; its activity is low in the dark-adapted state but increases dramatically on light adaptation10–12. The resulting drop in cyclic GMP content could serve as a chemical ‘signal’ in the normal visual process13,14. 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 retina15,16. 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 dysplasia15 that could lead to greatly increased cyclic GMP content, as had been reported in mice with inherited retinal degeneration16. 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.