Cyclic AMP Resets the Circadian Clock in Cultured Xenopus Retinal Photoreceptor Layers

Abstract

The Xenopus retinal photoreceptor layer contains a circadian oscillator that regulates melatonin synthesis in vitro. The phase of this oscillator 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 can inhibit adenylate cyclase in retinal photoreceptors, suggesting cyclic AMP as a candidate second messenger for entrainment of the circadian oscillator. We report here that treatments that increase intracellular cyclic AMP reset the phase of the photoreceptor circadian oscillator, and that the phase‐response curves for these treatments are 180° out of phase with the phase‐response curves for light and dopamine. Activation of adenylate cyclase by forskolin during the late subjective day or early subjective night caused phase advances. The same treatment during the late subjective night or early subjective day caused phase delays. Similar phase shifts were induced by 3‐isobutyl‐1‐methyl‐xanthine (a phosphodiesterase inhibitor) or 8‐(4‐chlorophenylthio)cyclic AMP. All of these treatments also acutely increased melatonin release. Forskolin and 3‐isobutyl‐1‐methylxanthine increased the accumulation of intracellular cyclic AMP, but not cyclic GMP, in photoreceptor layers. The results indicate that cyclic AMP‐dependent pathways regulate the photoreceptor circadian oscillator and suggest that a decrease in cyclic AMP may be involved in circadian entrainment by light and/or dopamine.

Circadian Regulation of cGMP-Gated Channels of Vertebrate Cone Photoreceptors: Role of cAMP and Ras

“…Similarly, there is evidence that cAMP can stimulate retinomotor movements (Besharse et al, 1982;Burnside et al, 1982;Burnside and Ackland, 1984;Burnside, 2001), but it is not known whether cAMP drives the circadian rhythm in this process. It should also be noted that cAMP can reset the circadian oscillators of Xenopus retinal photoreceptors (Hasegawa and Cahill, 1998). Clock resetting caused by altered cAMP signaling cannot explain our results, because the treatment durations that we used are short compared with a circadian cycle, and we observed robust effects of cAMP protagonists on CNGCs, Ras, and Erk activities without altering cPer2 mRNA levels.…”

“…8). Note that this does not exclude that cAMP can phase-shift the retinal oscillator, indeed it is known to do so in Xenopus retinal photoreceptors (Hasegawa and Cahill, 1998). However, the consequences of clock phase-shifting would normally be observed on subsequent cycles, rather than immediately after cessation of a 2 hr drug treatment.…”

Circadian Regulation of nocturnin Transcription by Phosphorylated CREB in Xenopus Retinal Photoreceptor Cells

“…In hamster retina, cAMP levels are also rhythmic, but its levels were examined only under cyclic light conditions (16). However, within the Xenopus retina, although changing levels of cAMP are clearly involved in the phaseshifting effects of dopamine, it is not clear whether cAMP levels fluctuate with a circadian rhythm (28)(29)(30). It is known that dopamine from inner retinal neurons acts through D2-like dopamine receptors on photoreceptors (8,45) to reset the clock.…”

Coregulation of Glutamate Uptake and Long-Term Sensitization inAplysia

“…To determine concentrations of cAMP in clusters of sensory neurons, radioimmunoassay was used as described (Hasegawa and Cahill, 1998). Pleural-pedal ganglia were dissected, and sensory neuron clusters were treated as described above.…”