Regulation of cAMP by light and dopamine receptors is dysfunctional in photoreceptors of dystrophic retinal degeneration slow (rds) mice

cAMP levels in dark and light were studied in dystrophic retinal degenerati on slow (rds) mice, which carry a mutation in the rds/peripherin gene, cAMP levels were measured in vivo, in freshly isolated retinas, and in vitro in the presence of glutamate, which confines light modulation to photorecepto rs. Experiments were conducted on young animals, when significant numbers o f viable photoreceptor cells are present. In vivo levels of cAMP are higher in illuminated rds/rds retinas than levels measured in normal BALB/c retin as. Light-evoked down-regulation of cAMP levels was observed in vitro in no rmal photoreceptors. These measurements were made in the presence of the cy clic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine; t herefore, they reflect an inhibition of cAMP formation. In contrast, light had no effect on cAMP formation in photoreceptors of mutant mice, measured under identical conditions. Thus, elevated levels of cAMP in rds/rds retina s in vivo result from abnormalities in cAMP synthesis in the mutant photore ceptor cells. In addition to regulation by light, cAMP formation in photore ceptor cells is regulated by dopamine, acting through dopamine D4 receptors . A dopamine D2/ D4 receptor agonist, quinpirole, reduced cAMP levels in da rk-adapted normal retinas in vitro, but not in rds/rds retinas. Our data in dicate that alterations in a signal transduction pathway that leads to inhi bition of adenylyl cyclase might underlie the abnormalities in cAMP levels in mutant rds/rds retinas. Heterozygous rds/+ photoreceptors demonstrated a normal pattern of light-evoked and quinpirole-mediated down-regulation of cAMP. Thus, partial expression of the normal phenotype is sufficient to ren der normal characteristics of cAMP regulation to the photoreceptors of the heterozygous mouse. The data obtained in the present study might be relevan t to the understanding of photoreceptor pathology of patients with peripher in/rds mutations, (C) 2001 Academic Press.