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Vertebrate eyes are known to contain circadian clocks, however, the intracellular mechanisms regulating the retinal clockwork remain largely unknown. To address this, we generated a cell line (hRPE-YC) from human retinal pigmental epithelium, which stably co-expressed reporters for molecular clock oscillations ( Bmal1-luciferase ) and intracellular Ca 2+  concentrations ( YC3.6 ). The hRPE-YC cells demonstrated circadian rhythms in  Bmal1  transcription. Also, these cells represented circadian rhythms in Ca 2+ -spiking frequencies, which were canceled by dominant-negative  Bmal1  transfections. The muscarinic agonist carbachol, but not photic stimulation, phase-shifted  Bmal1  transcriptional rhythms with a type-1 phase response curve. This is consistent with significant  M3  muscarinic receptor expression and little photo-sensor ( Cry2  and  Opn4 ) expression in these cells. Moreover, forskolin phase-shifted  Bmal1  transcriptional rhythm with a type-0 phase response curve, in accordance with long-lasting CREB phosphorylation levels after forskolin exposure. Interestingly, the hRPE-YC cells demonstrated apparent circadian rhythms in phagocytic activities, which were abolished by carbachol or dominant-negative  Bmal1  transfection. Because phagocytosis in RPE cells determines photoreceptor disc shedding, molecular clock oscillations and cytosolic Ca 2+  signaling may be the driving forces for disc-shedding rhythms known in various vertebrates. In conclusion, the present study provides a cellular model to understand molecular and intracellular signaling mechanisms underlying human retinal circadian clocks.

Regulation of molecular clock oscillations and phagocytic activity via muscarinic Ca2+ signaling in human retinal pigment epithelial cells