Regulation of CREB Phosphorylation in the Suprachiasmatic Nucleus by Light and a Circadian Clock

TLDR

Circadian rhythms are governed by the SCN pacemaker, but the molecular mechanisms synchronizing it are unknown, though SCN immediate early gene expression correlates with entrainment. The authors isolated antibodies that detect the phosphorylated form of the transcription factor CREB. Light rapidly phosphorylates CREB at Ser133 in the SCN only during circadian phases that induce IEG expression and phase shifts, implicating CREB in light‑mediated neuronal signaling and indicating that circadian gating of light responses occurs upstream of CREB phosphorylation.

Abstract

Mammalian circadian rhythms are regulated by a pacemaker within the suprachiasmatic nuclei (SCN) of the hypothalamus. The molecular mechanisms controlling the synchronization of the circadian pacemaker are unknown; however, immediate early gene (IEG) expression in the SCN is tightly correlated with entrainment of SCN-regulated rhythms. Antibodies were isolated that recognize the activated, phosphorylated form of the transcription factor cyclic adenosine monophosphate response element binding protein (CREB). Within minutes after exposure of hamsters to light, CREB in the SCN became phosphorylated on the transcriptional regulatory site, Ser 133 . CREB phosphorylation was dependent on circadian time: CREB became phosphorylated only at times during the circadian cycle when light induced IEG expression and caused phase shifts of circadian rhythms. These results implicate CREB in neuronal signaling in the hypothalamus and suggest that circadian clock gating of light-regulated molecular responses in the SCN occurs upstream of phosphorylation of CREB.