The Phosphorylation of CREB at Serine 133 Is a Key Event for Circadian Clock Timing and Entrainment in the Suprachiasmatic Nucleus

Abstract

Within the suprachiasmatic nucleus (SCN)-the locus of the master circadian clock-transcriptional regulation via the CREB/CRE pathway is implicated in the functioning of the molecular clock timing process, and is a key conduit through which photic input entrains the oscillator. One event driving CRE-mediated transcription is the phosphorylation of CREB at serine 133 (Ser 133). Indeed, numerous reporter gene assays have shown that an alanine point mutation in Ser 133 reduces CREB-mediated transcription. Here, we sought to examine the contribution of Ser 133 phosphorylation to the functional role of CREB in SCN clock physiology in vivo. To this end, we used a CREB knock-in mouse strain, in which Ser 133 was mutated to alanine (S/A CREB). Under a standard 12 h lightdark cycle, S/A CREB mice exhibited a marked alteration in clock-regulated wheel running activity. Relative to WT mice, S/A CREB mice had highly fragmented bouts of locomotor activity during the night phase, elevated daytime activity, and a delayed phase angle of entrainment. Further, under free-running conditions, S/A CREB mice had a significantly longer tau than WT mice and reduced activity amplitude. In S/A CREB mice, light-evoked clock entrainment, using both Aschoff type 1 and 6 h "jet lag" paradigms, was markedly reduced relative to WT mice. S/A CREB mice exhibited attenuated transcriptional drive, as assessed by examining both clock-gated and light-evoked gene expression. Finally, SCN slice culture imaging detected a marked disruption in cellular clock phase synchrony following a phase-resetting stimulus in S/A CREB mice. Together, these data indicate that signaling through CREB phosphorylation at Ser 133 is critical for the functional fidelity of both SCN timing and entrainment.

The eIF2α Kinase GCN2 Modulates Period and Rhythmicity of the Circadian Clock by Translational Control of Atf4

“…CREB is a key regulator of the circadian clock. CREB activities are important for SCN clock entrainment (Wheaton et al, 2018;Gau et al, 2002) as well as autonomous rhythmicity (Wheaton et al, 2018;Lee at al., 2010). Activated CREB binds to CREs and promotes CRE-mediated gene transcription (Sakamoto et al, 2011).…”

Systemic injection of an H4 receptor agonist induces a decrease in CREB and pCREB levels in the cerebellar vermis and prefrontal cortex in mice

“…In addition to the role of CREB in the formation of memories (12), it is known that CREB phosphorylation is involved in many adaptive behaviors that we cannot exclude triggering the transcription of circadian genes that will act on the circadian rhythm and could influence an animal's performance (10). In the present study, we injected saline or drug solutions in animals at the same time of day to minimize this bias.…”

“…As is well-known, the phosphorylation-induced activation of the cellular transcription factor cyclic AMP response element binding (CREB) protein is a necessary component of memory formation and cognitive processes (9). In addition to the memory formation, CREB also demonstrated an important role in many complex behaviors, including circadian rhythm, and its activity depends on the encephalic region that is involved (10).…”

Contraction influences Per2 gene expression in skeletal muscle through a calcium‐dependent pathway

“…CREB phosphorylation plays a role in regulating the response of the SCN clock to stimuli such as light (Gau et al 2002;Wheaton et al 2018). A CRE has been identified in the Per2 promoter (Impey et al 2004) and Per isoforms are driven by CREB binding to CREs in promoter regions (Tischkau et al 2003;Pulivarthy et al 2007).…”