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 degeneration 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 photoreceptors. Experiments were conducted on young animals, when significant numbers of viable photoreceptor cells are present. In vivo levels of cAMP are higher in illuminated rds/rds retinas than levels measured in normal BALB/c retinas. Light-evoked down-regulation of cAMP levels was observed in vitro in normal photoreceptors. These measurements were made in the presence of the cyclic nucleotide phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine; therefore, 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 retinas in vivo result from abnormalities in cAMP synthesis in the mutant photoreceptor cells. In addition to regulation by light, cAMP formation in photoreceptor cells is regulated by dopamine, acting through dopamine D4 receptors. A dopamine D2/D4 receptor agonist, quinpirole, reduced cAMP levels in dark-adapted normal retinas in vitro, but not in rds/rds retinas. Our data indicate that alterations in a signal transduction pathway that leads to inhibition 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 render normal characteristics of cAMP regulation to the photoreceptors of the heterozygous mouse. The data obtained in the present study might be relevant to the understanding of photoreceptor pathology of patients with peripherin/rds mutations.
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Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX, USA.
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Iuvone
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D000262:Adenylyl Cyclases / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D003623:Dark Adaptation; D018491:Dopamine Agonists / Q000494:pharmacology; D015536:Down-Regulation; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D019257:Quinpirole / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000378:metabolism*; D012162:Retinal Degeneration / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology
D018491:Dopamine Agonists; D010726:Phosphodiesterase Inhibitors; D011954:Receptors, Dopamine; D014970:Xanthines; D019257:Quinpirole; C008514:methylxanthine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases