Calcium modulates circadian variation in cAMP-stimulated melatonin in chick pineal cells

In chick pineal cells, melatonin synthesis is regulated by both calcium and cAMP. Calcium-dependent regulation of melatonin is suggested by the monotonic decrease in melatonin observed with decreasing extracellular calcium ion concentrations ([Ca²⁺](o)), the stimulation of melatonin with Bay K8644, and the inhibition of nocturual melatonin by several calmodulin antagonists. At submicromolar [Ca²⁺](o), a stimulation of melatonin was observed in the presence of 8-Br cAMP, but not with Bay K8644, suggesting that this amount of stimulation of melatonin by 8-Br cAMP is independent of Ca²⁺ influx through dihydropyridine-sensitive Ca²⁺ channels. At micromolar [Ca²⁺](o), there was a further increase in the stimulation of melatonin by 8-Br cAMP that was not blocked by nifedipine, a dihydropyridine-sensitive Ca²⁺ channel antagonist. Micromolar [Ca²⁺](o) is required for the greater stimulation of melatonin by 8-Br cAMP during the night than during the day. Melatonin was stimulated by 8-Br cAMP to higher levels during the night than during the subjective day under normal [Ca²⁺](o) (1.3 mM). This difference in the amount of melatonin stimulated by 8-Br cAMP during the subjective night versus the subjective day was blocked by lowering [Ca²⁺](o) to a submicromolar concentration (0.2 μM). Both nifedipine and calmidazolium partially blocked nocturnal increases in melatonin, but were ineffective during the day. These results suggest that Ca²⁺ plays an important role in the differential ability of cAMP to stimulate melatonin during the night versus the day.