Ca2+/cAMP Response Element-binding Protein (CREB)-dependent Activation of Per1 Is Required for Light-induced Signaling in the Suprachiasmatic Nucleus Circadian Clock

Abstract

Light is a prominent stimulus that synchronizes endogenous circadian rhythmicity to environmental light/ dark cycles. Nocturnal light elevates mRNA of the Period1 (Per1) gene and induces long term state changes, expressed as phase shifts of circadian rhythms. The cellular mechanism for Per1 elevation and light-induced phase advance in the suprachiasmatic nucleus (SCN), a process initiated primarily by glutamatergic neurotransmission from the retinohypothalamic tract, was examined. Glutamate (GLU)-induced phase advances in the rat SCN were blocked by antisense oligodeoxynucleotide (ODN) against Per1 and Ca 2؉ /cAMP response element (CRE)-decoy ODN. CRE-decoy ODN also blocked light-induced phase advances in vivo. Furthermore, the CRE-decoy blocked GLU-induced accumulation of Per1 mRNA. Thus, Ca 2؉ /cAMP response element-binding protein (CREB) and Per1 are integral components of the pathway transducing light-stimulated GLU neurotransmission into phase advance of the circadian clock.Mammalian circadian rhythmicity is generated by endogenous alternations in transcription/translation of putative clock genes within the suprachiasmatic nucleus (SCN) 1 of the basal hypothalamus. As a projection site of the retinohypothalamic tract, the SCN is poised to respond to retinal light information, mediated primarily by glutamatergic (GLU) neurotransmission, to assure time-of-day congruence between the endogenous pacemaker and the external environment. The mechanisms by which the SCN decodes and processes light information are complex and change as the biochemical clock states progress through their 24-h cycle (1). Light resets the clock throughout the night via glutamatergic-N-methyl-D-aspartate receptor-mediated Ca 2ϩ influx, which activates nitric-oxide synthase to liberate nitric oxide (NO) (2). At this point, the light signaling pathway diverges. In the early night, the light-induced state change, which delays subsequent rhythms, proceeds through NO-dependent activation of a neuronal ryanodine receptor. Light-induced state changes in the late night are independent of ryanodine receptor activation, but require activation of protein kinase G (PKG) (3-5). The discovery of several specific genes associated with circadian rhythmicity, including Period (Per) and Timeless (Tim) (for review, see Ref. 6), raises questions regarding the mechanisms that interface nocturnal light signals with the molecular clockwork. Throughout the night, light stimuli sufficient to cause long term state changes, or phase shifts, of circadian rhythms of rodent wheel running correlate with increased phosphorylation of the transcription factor, Ca 2ϩ /cAMP response element-binding protein (CREB) (7, 8), activation of Ca 2ϩ /cAMP response element (CRE)-mediated transcription (9), and a rise in Per1 mRNA (10 -15). This investigation was undertaken to determine whether CRE-mediated activation of Per1 is required for light/GLU-induced phase resetting of the SCN clock. We hypothesized that the GLU-induced phase advance requires activation of CRE and elevation ...

Gene expression patterns define key transcriptional events in cell-cycle regulation by cAMP and protein kinase A

“…Several circadian rhythm clock genes (Table 1) were identified in early-induction cluster 1. Of these clock genes identified by MAPPFINDER in cluster 1, only Per1 was significantly induced by 2 h (4-fold induction; P Ͻ 0.05), consistent with a previous report (24). Per1 is under circadian regulation in human and mouse peripheral tissues (25,26) and is responsible, in part, for maintaining core clock rhythm.…”

Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells

“…CREB-dependent signaling regulates Per promoters (58), being regulation necessary for lightinduced signaling and phase shifts in the SCN (2,59). In addition, CREB activation was shown to be involved in the generation of circadian clock gene expression in rat fibroblasts (43), suggesting a role for the CRE/CREB pathway also in peripheral tissues.…”

Differential Response of Period 1 Expression within the Suprachiasmatic Nucleus

“…The clock genes Period 1 (Per1) and Per2, which exhibit circadian expression within the SCN, appear to play a key role in lightinduced resetting of the mammalian clock, insomuch as both genes are rapidly induced after light stimulation at night (Albrecht et al, 1997;Shearman et al, 1997;Shigeyoshi et al, 1997;Tei et al, 1997). Induction of Per1 is required for light/glutamateinduced phase shifts in both early (Akiyama et al, 1999) and late night (Tischkau et al, 2003). After a shift in the light schedule, circadian rhythms reentrain to the new light/dark (LD) cycle, although a complete readjustment can take several cycles, especially for phase advances.…”