Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior

Seluzicki, Adam; Flourakis, Matthieu; Kula-Eversole, Elżbieta; Zhang, Luoying; Kilman, Valerie L.; Allada, Ravi

doi:10.1371/journal.pbio.1001810

Cited by 114 publications

(153 citation statements)

References 79 publications

(111 reference statements)

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“…As expected of a family B1 GPCR, PDFR activation elevates cAMP and calcium levels (Hyun et al, 2005;Mertens et al, 2005). RNA interference studies revealed that protein kinase A is normally activated by PDF activity and likely promotes stability and cycling of the essential clock proteins TIMELESS (Seluzicki et al, 2014) and PERIOD (Li et al, 2014). Furthermore, GW182, which mediates microRNAdependent gene silencing through its interaction with AGO1, modulates PDFR signaling by silencing the expression of DUNCE, a cAMP phosphodiesterase (Zhang and Emery, 2013).…”

Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 95%

Model Organisms in G Protein–Coupled Receptor Research

et al. 2015

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The study of G protein-coupled receptors (GPCRs) has benefited greatly from experimental approaches that interrogate their functions in controlled, artificial environments. Working in vitro, GPCR receptorologists discovered the basic biologic mechanisms by which GPCRs operate, including their eponymous capacity to couple to G proteins; their molecular makeup, including the famed serpentine transmembrane unit; and ultimately, their three-dimensional structure. Although the insights gained from working outside the native environments of GPCRs have allowed for the collection of low-noise data, such approaches cannot directly address a receptor's native (in vivo) functions. An in vivo approach can complement the rigor of in vitro approaches: as studied in model organisms, it imposes physiologic constraints on receptor action and thus allows investigators to deduce the most salient features of receptor function. Here, we briefly discuss specific examples in which model organisms have successfully contributed to the elucidation of signals controlled through GPCRs and other surface receptor systems. We list recent examples that have served either in the initial discovery of GPCR signaling concepts or in their fuller definition. Furthermore, we selectively highlight experimental advantages, shortcomings, and tools of each model organism.

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Section: Animal Models To Discover and Validate Molecular Conceptsmentioning

confidence: 95%

Model Organisms in G Protein–Coupled Receptor Research

et al. 2015

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“…Interestingly, PDFR signaling through ACIII is limited to one subset of circadian clock neurons, while signaling through ACVIII in another (Duvall and Taghert 2013). PDFR activation in a target cell induces two parallel signaling pathways downstream of cAMP: protein kinase A (PKA)-dependent regulation of the clock component TIMELESS and PKA-independent regulation of target neurons electrical excitability (Seluzicki et al 2014). Perhaps related to the independence of these two pathways, it was recently shown that Drosophila circadian clock neurons with the same phase of molecular oscillation can show very different phases of intracellular Ca 2þ , and their specific phase relationships are determined by PDF/PDFR signaling (Liang et al 2016).…”

Section: Action Potential Activation Of Signaling Pathwaysmentioning

confidence: 99%

Membrane Currents, Gene Expression, and Circadian Clocks

Allen

Nitabach

Colwell

2017

Cold Spring Harb Perspect Biol

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Neuronal circadian oscillators in the mammalian and Drosophila brain express a circadian clock comprised of interlocking gene transcription feedback loops. The genetic clock regulates the membrane electrical activity by poorly understood signaling pathways to generate a circadian pattern of action potential firing. During the day, Na þ channels contribute an excitatory drive for the spontaneous activity of circadian clock neurons. Multiple types of K þ channels regulate the action potential firing pattern and the nightly reduction in neuronal activity. The membrane electrical activity possibly signaling by changes in intracellular Ca 2þ and cyclic adenosine monophosphate (cAMP) regulates the activity of the gene clock. A decline in the signaling pathways that link the gene clock and neural activity during aging and disease may weaken the circadian output and generate significant impacts on human health. N eurons in the suprachiasmatic nucleus (SCN) function as part of a central timing circuit that drives daily changes in our behavior and underlying physiology. A hallmark feature of SCN neurons is that they are electrically silent during the night, start firing action potentials near dawn, and then continue to generate action potentials with a slow and steady pace all day long. These rhythms in electrical activity are critical for the function of the circadian timing system. This article reviews what is known about the ionic and molecular mechanisms driving the rhythmic firing patterns in our body's clock. We raise the hypothesis that a decline in neural activity in the central clock may be a critical mechanism by which aging and disease may weaken the circadian output and contribute to a set of symptoms that impacts human health. THE IONIC MECHANISMS UNDERLYING NEURAL ACTIVITY RHYTHMSSCN neurons generate action potentials in the absence of synaptic drive, and can therefore be considered endogenously active neurons.

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“…Assuming rhythmic bimodal dominance of either PDFR or NPFR1 GPCRs in s-LNvs, or simply the expression of one of the receptors in a given cluster, PER oscillations in a neuron can be regulated or reinforced by signals from other circadian neurons. Another cAMP-responsive protein, protein kinase A (PKA), stabilizes PER and TIM in high cAMP conditions (Li et al 2014;Seluzicki et al 2014). Thus, a model for PER accumulation that incorporates cAMP activity can be proposed.…”

Section: Coordination Between Differentially Regulated Circadian Clocksmentioning

confidence: 99%

“…In circadian rhythms, PKA deficiencies lead to a loss of locomotor rhythmicity in flies (∼80% arrhythmic), while per RNA oscillation and eclosion rhythmicity remains intact (Majercak et al 1997), indicating that PKA is involved in output mechanisms that specifically regulate locomotor rhythmicity. PKA activity is required to stabilize TIM in some clock neurons (LNds and DN1s) and stabilize PER in other clock neurons (LNvs) (Li et al 2014;Seluzicki et al 2014), offering a basis for observed behavioral arrhythmicity, but without a satisfactory explanation for how eclosion remains rhythmic. The molecular basis for cell-type-specific differences by which PKA stabilizes TIM and PER are not understood.…”

Section: Other Kinasesmentioning

confidence: 99%

“…Like SGG, PKA may transduce extracellular signals of the CCNN to influence the stability of the repressor complex to regulate clock phase or synchrony. Whereas extracellular signaling through SGG affects nuclear entry of the TIM/PER repressor complex and alters the onset of transcriptional repression (Martinek et al 2001;Top et al 2016), PKA signaling alters TIM and PER stability, impacting the termination of transcriptional repression (Li et al 2014;Seluzicki et al 2014), suggesting that these pathways may regulate target genes at different times of day.…”

Section: Other Kinasesmentioning

confidence: 99%

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Coordination between Differentially Regulated Circadian Clocks Generates Rhythmic Behavior

Top

Young

2017

Cold Spring Harb Perspect Biol

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Specialized groups of neurons in the brain are key mediators of circadian rhythms, receiving daily environmental cues and communicating those signals to other tissues in the organism for entrainment and to organize circadian physiology. In Drosophila, the "circadian clock" is housed in seven neuronal clusters, which are defined by their expression of the main circadian proteins, Period, Timeless, Clock, and Cycle. These clusters are distributed across the fly brain and are thereby subject to the respective environments associated with their anatomical locations. While these core components are universally expressed in all neurons of the circadian network, additional regulatory proteins that act on these components are differentially expressed, giving rise to "local clocks" within the network that nonetheless converge to regulate coherent behavioral rhythms. In this review, we describe the communication between the neurons of the circadian network and the molecular differences within neurons of this network. We focus on differences in protein-expression patterns and discuss how such variation can impart functional differences in each local clock. Finally, we summarize our current understanding of how communication within the circadian network intersects with intracellular biochemical mechanisms to ultimately specify behavioral rhythms. We propose that additional efforts are required to identify regulatory mechanisms within each neuronal cluster to understand the molecular basis of circadian behavior. C ircadian rhythms are behavioral and physiological responses that allow anticipation of daily changes in the environment, such as day/ night cycles. Indeed, circadian rhythms are entrained by diurnal oscillations in light, temperature, and food availability, each of which can be considered a "zeitgeber," or "time giver." Such anticipatory behavior of daily events confers adaptive advantages on individuals that organize physiology around planetary rhythms, as well as within a species as a whole, for purposes of mating, cooperation, protection, etc. In a sense, rhythmic anticipation can be thought of as a primitive mechanism of planning and cognition.The circadian clock, consisting of transcriptional negative feedback loops, underlies the regulation of a ∼24-h behavioral rhythm. The molecular architecture of this feedback loop is conserved across the majority of multicellular organisms. In animals, the "master clock" is housed in specialized pacemaker neurons in the brain that coordinate various "peripheral clocks" throughout the organism to regulate daily physiological and behavioral changes.

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Dual PDF Signaling Pathways Reset Clocks Via TIMELESS and Acutely Excite Target Neurons to Control Circadian Behavior

Abstract: Studies in Drosophila circadian neurons reveal a bifurcation in the Pigment Dispersing Factor (PDF) neuropeptide signaling pathway, independently synchronizing circadian clocks via PKA or acutely controlling neuronal excitability via cAMP.

Cited by 114 publications

References 79 publications

Model Organisms in G Protein–Coupled Receptor Research

Model Organisms in G Protein–Coupled Receptor Research

Membrane Currents, Gene Expression, and Circadian Clocks

Coordination between Differentially Regulated Circadian Clocks Generates Rhythmic Behavior

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