The VPAC2 Receptor Is Essential for Circadian Function in the Mouse Suprachiasmatic Nuclei

Harmar, Anthony J.; Marston, Hugh; Shen, Sanbing; Spratt, Christopher; Km, West; Sheward, W. J.; Morrison, Christine F.; Dorin, Julia R.; Piggins, Hugh D.; Reubi, Jean Claude; Kelly, John; Maywood, Elizabeth S.; Hastings, Michael H.

doi:10.1016/s0092-8674(02)00736-5

Cited by 504 publications

(518 citation statements)

References 49 publications

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“…The competence of the SCN as a circadian pacemaker in prokr2 Brdm1 mutants contrasts markedly with its disorganization in mice lacking the Vpac2 receptor for VIP (18), a neuropeptide coexpressed with Prok2 in SCN cells (21). In Vpac2-null mice, the amplitude of circadian gene expression is reduced by Ͼ90%; half of SCN cells are arrhythmic, and the remainder express poorly defined, asynchronous cycles (19).…”

Section: Discussionmentioning

confidence: 99%

“…3e) and general activity (data not shown), and interdaily stability was reduced (mean Ϯ SEM: m/m, 0.53 Ϯ 0.04; ϩ/m, 0.63 Ϯ 0.07; ϩ/ϩ, 0.73 Ϯ 0.05; P Ͻ 0.05). In contrast to the effects of mutation to several core clock genes, the quality of the rhythm did not deteriorate further with prolonged exposure to DD, nor was there evidence of a multiplicity of periods, in contrast to mice lacking the Vpac2 receptor for vasoactive intestinal peptide (VIP) (17,18).…”

Section: Loss Of Prokr2mentioning

confidence: 96%

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Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prosser

Bradley

Chesham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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133

138

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The suprachiasmatic nucleus (SCN), the brain's principal circadian pacemaker, coordinates adaptive daily cycles of behavior and physiology, including the rhythm of sleep and wakefulness. The cellular mechanism sustaining SCN circadian timing is well characterized, but the neurochemical pathways by which SCN neurons coordinate circadian behaviors remain unknown. SCN transplant studies suggest a role for (unidentified) secreted factors, and one potential candidate is the SCN neuropeptide prokineticin 2 (Prok2). Prok2 and its cognate prokineticin receptor 2 (Prokr2/Gpcr73l1) are widely expressed in both the SCN and its neural targets, and Prok2 is light-regulated. Hence, they may contribute to cellular timing within the SCN, entrainment of the clock, and/or they may mediate circadian output. We show that a targeted null mutation of Prokr2 disrupts circadian coordination of the activity cycle and thermoregulation. Specifically, mice lacking Prokr2 lost precision in timing the onset of nocturnal locomotor activity; and under both a light/dark cycle and continuous darkness, there was a pronounced temporal redistribution of activity away from early to late circadian night. Moreover, the coherence of circadian behavior was significantly reduced, and nocturnal body temperature was depressed. Entrainment by light is not, however, dependent on Prokr2, and bioluminescence real-time imaging of organotypical SCN slices showed that the mutant SCN is fully competent as a circadian oscillator. We conclude that Prokr2 is not necessary for SCN cellular timekeeping or entrainment, but it is an essential link for coordination of circadian behavior and physiology by the SCN, especially in defining the onset and maintenance of circadian night.T he suprachiasmatic nucleus (SCN) of the hypothalamus constitutes an autonomous circadian pacemaker necessary for the maintenance of daily rhythms, including the cycle of sleep and wakefulness (1). The molecular basis of the cellular oscillator of the SCN is broadly characterized, but how the SCN signals circadian time to other sites in the brain and thence to peripheral tissues is unclear (2). Neuroanatomical projections from the SCN run predominantly to local hypothalamic and thalamic structures (3), including the dorsomedial nucleus (DMN), a principal site for the regulation of sleep and wakefulness and circadian arousal by behavioral cues (4, 5). How such ''hard-wired'' connections influence SCN targets remains open to question. Although electrical signaling by means of synaptic contacts is likely important (6), encapsulated SCN grafts unable to form synaptic contacts with host tissues are nevertheless able to establish circadian activity/rest cycles in previously arrhythmic, SCN-lesioned recipients (7). This finding indicates that paracrine factors from the SCN mediate circadian coordination within the brain. A small number of candidate factors have been explored, including TGF-␣ (8) and cardiotrophin-like cytokine (9). These factors are expressed by the SCN on a circadian basis, and local ...

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Section: Discussionmentioning

confidence: 99%

Section: Loss Of Prokr2mentioning

confidence: 96%

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prosser

Bradley

Chesham

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

133

138

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“…Notably, Gpr176 is expressed mainly in the brain, with most being found in the SCN, and its protein abundance within the SCN fluctuates in a circadian fashion, peaking during the night. More specifically, Gpr176 colocalizes with the vasoactive intestinal peptide (Vip) receptor Vipr2, a receptor known to play a key role in circadian timing [19,20]. Temporal expression profiles of Gpr176 and Vipr2 reveal that while these two receptors exist in the same SCN neurons, they are opposite in peak expression phase.…”

Section: Gpr176 Cycles In Abundance and Colocalizes With Vipr2mentioning

confidence: 99%

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

et al. 2017

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Abstract. G-protein-coupled receptors (GPCRs) constitute an immensely important class of drug targets with diverse clinical applications. There are still more than 120 orphan GPCRs whose cognate ligands and physiological functions are not known. A set of circadian pacemaker neurons that governs daily rhythms in behavior and physiology resides in the suprachiasmatic nucleus (SCN) in the brain. Malfunction of the circadian clock has been linked to a multitude of diseases, such as sleeping disorders, obesity, diabetes, cardiovascular diseases, and cancer, which makes the clock an attractive target for drug development. Here, we review a recently identified role of Gpr176 in the SCN. Gpr176 is an SCN-enriched orphan GPCR that sets the pace of the circadian clock in the SCN. Even without known ligand, this orphan receptor has an agonist-independent basal activity to reduce cAMP signaling. A unique cAMP-repressing G-protein subclass Gz is required for the activity of Gpr176. We also provide an overview on the circadian regulation of G-protein signaling, with an emphasis on a role for the regulator of G-protein signaling 16 (RGS16). RGS16 is indispensable for the circadian regulation of cAMP in the SCN. Developing drugs that target the SCN remains an unfulfilled opportunity for the circadian pharmacology. This review argues for the potential impact of focusing on GPCRs in the SCN for the purpose of tuning the body clock.

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“…120 Both peptides use the G-proteincoupled VPAC 2 receptor, and receptor knockout mutant mice show various types of circadian behavioural and molecular dysfunction. 121 Subsequent analyses reveal that neurons in the SCN may retain cycling clock gene expression, but the absence of the VPAC 2 receptor means that they are desynchronised with respect to each other. 122 Thus, VIP may, as with PDF in the LNs of the fly, represent a paracrine signal that maintains temporal order between SCN neurons.…”

Section: Functional Differences In Circadian Cellsmentioning

confidence: 99%

Molecular genetics of the fruit-fly circadian clock

2006

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The circadian clock percolates through every aspect of behaviour and physiology, and has wide implications for human and animal health. The molecular basis of the Drosophila circadian clock provides a model system that has remarkable similarities to that of mammals. The various cardinal clock molecules in the fly are outlined, and compared to those of their actual and 'functional' homologues in the mammal. We also focus on the evolutionary tinkering of these clock genes and compare and contrast the neuronal basis for behavioural rhythms between the two phyla.

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The VPAC2 Receptor Is Essential for Circadian Function in the Mouse Suprachiasmatic Nuclei

Cited by 504 publications

References 49 publications

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei

G-protein-coupled receptor signaling through Gpr176, Gz, and RGS16 tunes time in the center of the circadian clock [Review]

Molecular genetics of the fruit-fly circadian clock

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