Pituitary adenylyl cyclase-activating peptide: A pivotal modulator of glutamatergic regulation of the suprachiasmatic circadian clock

Chen, Dong; Buchanan, Gordon F.; Ding, Jian; Hannibal, Jens; Gillette, Martha U.

doi:10.1073/pnas.96.23.13468

Cited by 166 publications

(139 citation statements)

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“…Photic cues are transmitted to the SCN via the retinohypothalamic tract (RHT) (32) and entrain the SCN and its output rhythms to a 24-h day cycle. PACAP is abundant in the rat SCN, the RHT, and retinal ganglionic cells (32,33), and it has been shown to reset the circadian clock in a manner similar to light (34,35). Taken together, these reports suggest an involvement of PACAP in the regulation of central circadian rhythm in the mammalian SCN.…”

Section: Discussionmentioning

confidence: 74%

Regulation of Pituitary Adenylate Cyclase-activating Polypeptide Gene Transcription by TTF-1, a Homeodomain-containing Transcription Factor

Kim¹,

Hur²,

Son³

et al. 2002

Journal of Biological Chemistry

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is an important hypophysiotrophic factor as well as a regulator for immune, reproductive, and neural tissues. We recently found that TTF-1, a homeodomain-containing transcription factor essential for the development of the fetal diencephalon, is postnatally expressed in the hypothalamic area and plays a transcription regulatory role for certain neurohormones. Based on the similarity of synthesis sites between PACAP and TTF-1 and, moreover, on the presence of conserved core TTF-1 binding motifs in the 5-flanking region of the PACAP gene, we sought to uncover a regulatory role of TTF-1 in PACAP gene transcription. The TTF-1 homeodomain binds to six of the seven putative binding domains observed in the 5-flanking region of the PACAP gene. In the C6 glioma cell-line, TTF-1 activates the PACAP promoter in a dose-dependent manner. This transactivation of PACAP by TTF-1 was totally removed when the core TTF-1 binding motif at ؊369 was deleted. RNase protection assays showed that TTF-1 and PACAP mRNAs have daily fluctuations in the rat hypothalamus. They both were at low levels during the day and high levels during the night. Intracerebroventricular administration of an antisense TTF-1 oligodeoxynucleotide significantly decreased the PACAP mRNA level as well as TTF-1 protein content in the rat hypothalamus, suggesting that TTF-1 also regulates PACAP transcription in vivo. Moreover, the TTF-1 promoter was inhibited by molecular oscillators of CLOCK and BMAL-1. Taken together, these data suggest that TTF-1 plays an important regulatory role in the gene transcription for PACAP, which may be important for the generation of a daily rhythm of hypothalamic PACAP gene expression.Pituitary adenylate cyclase-activating polypeptide (PACAP) 1 was originally isolated from the ovine hypothalamus (1, 2) and was classified as a member of the secretin-glucagon-vasoactive intestinal peptide family (1). PACAP plays the role of a hypophysiotropic factor and regulates the synthesis and secretion of pituitary hormones through the hypothalamo-hypophysial portal system (3). Although PACAP immunoreactivity is found in nearly all brain regions, its highest concentration is in the hypothalamus of both rat and human (3, 4). In the hypothalamus, PACAP immunoreactivity is primarily localized to the cells of the paraventricular and supraoptic nuclei (3, 4). PACAP is found both in neurons terminating on hypophysial blood vessels of the median eminence as well as in neurons projecting to the posterior pituitary. Therefore, PACAP may act not only as a hypophysiotropic factor regulating anterior pituitary hormone release but as a posterior pituitary hormone as well. It is also an important factor in the regulation of peripheral tissues such as ovary and testis and of the immune system.Recently, the 5Ј-flanking region of PACAP gene was characterized and shown to have several sequence motifs homologous to the cAMP response element (CRE), the TPA response element (TRE), and the growth hormone factor...

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Section: Discussionmentioning

confidence: 74%

Regulation of Pituitary Adenylate Cyclase-activating Polypeptide Gene Transcription by TTF-1, a Homeodomain-containing Transcription Factor

Kim¹,

Hur²,

Son³

et al. 2002

Journal of Biological Chemistry

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“…We have previously shown that the neuropeptide pituitary adenylate cyclase activating peptide (PACAP) is costored with glutamate in the RHT (13) and that the two neurotransmitters are mediators of photic adjustment of the circadian system in a rather complex interplay (9). After the demonstration of PACAP in the RHT, (12) a number of studies have delineated the role of PACAP in light entrainment, which primarily seems to be exerted via the PACAPspecific PACAP receptor type 1 (PAC1) receptor (3,4,11,14,17,23). In vitro, PACAP has been shown to modulate glutamatergic signaling in a time-and concentration-dependent manner targeting the core clock genes Per1 and Per2 via cyclic AMP/PKA and the inositotriphospate/phospholipase C signaling pathway (reviewed in Ref.…”

mentioning

confidence: 99%

Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

Hannibal¹,

Brabet²,

Fahrenkrug³

2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Because of the prominent role of PACAP in signal transmission from the eye to the SCN in resetting of the circadian clock mechanism during the day (29,40,41), SCN tissue and SCN 2.2 cell cultures were examined for expression of PACAP type 1 receptor (PAC1-R, previously PVR1). PAC1-R is a G protein-linked sevenpass transmembrane receptor that activates adenylyl cyclase (AC) and/or phospholipase C (PLC) signaling pathways (35,36,42).…”

Section: Resultsmentioning

confidence: 99%

Immortalized Suprachiasmatic Nucleus Cells Express Components of Multiple Circadian Regulatory Pathways

Hurst

Earnest

Gillette

2002

Biochemical and Biophysical Research Communications

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We undertook an extensive antigenic characterization of the SCN 2.2 cell line in order to further evaluate whether the line expresses components of circadian regulatory pathways common to the hypothalamic suprachiasmatic nucleus (SCN), the central circadian clock in mammals. We found that differentiated SCN 2.2 cultures expressed a broad range of putative clock genes, as well as components of daytime, nighttime, and crepuscular circadian regulatory pathways found within the SCN in vivo. The line also exhibits several antigens that are highly expressed in a circadian pattern and/or differentially localized in the SCN relative to other hypothalamic regions. Expression of a broad complement of circadian regulatory proteins and putative clock genes further support growing evidence in recent reports that the SCN 2.2 cell line is an appropriate model for investigating the regulation of central mammalian pacemaker. © 2002 Elsevier Science (USA) Key Words: period; cryptochrome; casein kinase; PACAP; PKA; PKC; PKG; NOS; I1; VGF.The central biological pacemaker in mammals lies in the hypothalamic suprachiasmatic nucleus (SCN). The SCN drives circadian behavior, expresses rhythmic gene expression and integrates external stimuli in order to synchronize molecular timekeeping mechanisms with changing environmental conditions. Receptivity to phase shifting stimuli is gated by the circadian state of the central pacemaker. This gating behavior is most clearly demonstrated by the sensitivity of the SCN to light during the night phase, but not during the day phase. All photic, social and hormonal influences on the circadian clock are integrated at the cellular level through multiple signaling pathways within the SCN.The complexity of interacting signaling pathways involved in regulation of the SCN has encouraged researchers to seek cell culture systems to complement in vivo analysis of the mammalian circadian clock. Whether a cell line exhibits central or peripheral circadian clock characteristics complicates selection of an appropriate model system. To provide useful applications for central mammalian pacemaker research, cell line models must exhibit persistent self-sustained oscillations in circadian gene products, restore animal circadian rhythms in SCN-lesioned hosts and exhibit time-dependent responses to stimuli through regulatory pathways that characterize SCN function. Rhythmic gene expression has been demonstrated in NIH/ 3T3 fibroblasts, Rat-1 fibroblasts and spontaneously immortalized embryonic mouse fibroblasts after synchronizing signals (1-5). However, there is no published evidence that these lines express spontaneous, self-sustained rhythms or rescue rhythms in SCNlesioned animals (5, 6). In contrast, another cell line derived from fetal rat SCN, the SCN 2.2 cell line, exhibits endogenous spontaneous circadian rhythmicity in vitro (5, 7). We have focused on the SCN 2.2 line to further assess its usefulness as a model system for studying the mammalian central circadian pacemaker.The SCN 2.2 cell line is a pluripoten...

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Pituitary adenylyl cyclase-activating peptide: A pivotal modulator of glutamatergic regulation of the suprachiasmatic circadian clock

Cited by 166 publications

References 28 publications

Regulation of Pituitary Adenylate Cyclase-activating Polypeptide Gene Transcription by TTF-1, a Homeodomain-containing Transcription Factor

Regulation of Pituitary Adenylate Cyclase-activating Polypeptide Gene Transcription by TTF-1, a Homeodomain-containing Transcription Factor

Mice lacking the PACAP type I receptor have impaired photic entrainment and negative masking

Immortalized Suprachiasmatic Nucleus Cells Express Components of Multiple Circadian Regulatory Pathways

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