Retinal cAMP levels during the progression of retinal degeneration in rhodopsin P23H and S334ter transgenic rats.

摘要

PURPOSE: To test whether high levels of cAMP promote apoptosis and shorten the life of retinal rod photoreceptors, the changes in cAMP levels during retinal degeneration were analyzed in two transgenic rat models that express rhodopsin P23H and S334ter mutations. METHODS: Dark- and light-adapted heterozygous P23H (lines 1 and 3; P23H-1 and -3), S334ter line 4 (S334ter-4), and Sprague-Dawley (control) rats were studied at 4 to 8 weeks by cAMP enzyme competitive immunoassay and by cAMP immunocytochemistry. RESULTS: In control animals retinal cAMP content reached a steady state level at 30 days of age. Dark-adapted control retinas had up to 97% higher cAMP content than light-adapted retinas, and photoreceptor cells were the major source of this increase. Dark-adapted photoreceptors in all three lines of transgenic rats at advanced stages of retinal degeneration had cAMP content different from that of the control. In rats that express mutant rhodopsin, the number of photoreceptor cells was progressively reduced, because of retinal degeneration, but dark-adapted cAMP levels did not decline accordingly. P23H transgenic animals of both lines had higher levels of cAMP per photoreceptor cell count than control animals. This elevation was more pronounced as degeneration progressed. S334ter animals showed smaller cAMP elevation than P23H rats at a similar stage of retinal degeneration, but at a point when S334ter rats were undergoing rapid retinal degeneration, whereas in P23H rats retinal degeneration was slowing down. CONCLUSIONS: All three lines of transgenic rats carrying rhodopsin mutations show an increase in dark-adapted photoreceptor cAMP levels. A complex relationship exists between cAMP levels and the rate of cell death in the retina. Although initially higher levels of cAMP may promote cell survival and slow down retinal degeneration, ultimately, elevated cAMP levels may become toxic and may contribute to retinal cell death.