CYCLIC-AMP RESETS THE CIRCADIAN CLOCK IN CULTURED XENOPUS RETINAL PHOTORECEPTOR LAYERS

The Xenopus retinal photoreceptor layer contains a circadian oscillato r that regulates melatonin synthesis in vitro. The phase of this oscil lator can be reset by light or dopamine. The phase-response curves for light and dopamine are similar, with transitions from phase delays to phase advances in the mid-subjective night. Light and dopamine each c an inhibit adenylate cyclase in retinal photoreceptors, suggesting cyc lic AMP as a candidate second messenger for entrainment of the circadi an oscillator. We report here that treatments that increase intracellu lar cyclic AMP reset the phase of the photoreceptor circadian oscillat or, and that the phase-response curves for these treatments are 180 de grees out of phase with the phase-response curves for light and dopami ne. Activation of adenylate cyclase by forskolin during the late subje ctive day or early subjective night caused phase advances. The same tr eatment during the late subjective night or early subjective day cause d phase delays, Similar phase shifts were induced by 3-isobutyl-1-meth ylxanthine (a phosphodiesterase inhibitor) or 8-(4-chlorophenylthio)cy clic AMP. All of these treatments also acutely increased melatonin rel ease, Forskolin and 3-isobutyl-1-methylxanthine increased the accumula tion of intracellular cyclic AMP, but not cyclic GMP, in photoreceptor layers. The results indicate that cyclic AMP-dependent pathways regul ate the photoreceptor circadian oscillator and suggest that a decrease in cyclic AMP may be involved in circadian entrainment by light and/o r dopamine.