A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

Flourakis, Matthieu; Kula-Eversole, Elżbieta; Hutchison, Alan L.; Han, Tae Hee; Aranda, Kimberly; Moose, Devon L.; White, Kevin P.; Dinner, Aaron R.; Lear, Bridget C.; Ren, Dejian; Diekman, Casey O.; Raman, Indira M.; Allada, Ravi

doi:10.1016/j.cell.2015.07.036

Cited by 193 publications

(254 citation statements)

References 63 publications

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“…Modeling work using data from the action potential clamp also emphasizes the role of the Na þ leak in driving excitability in SCN neurons (Clay 2015). A recent experimental advance has been the description of a voltage-independent Na þ conductance via the NA/NALCN ion channel, which depolarizes both SCN neurons and Drosophila pacemaker neurons (Flourakis et al 2015). This study represents a significant advance as it provides the first evidence for the circadian regulation of an Na þ current.…”

Section: Daily Depolarizationmentioning

confidence: 91%

“…In Drosophila, circadian rhythms in mRNA encoding a regulatory protein associated with BK channels have been described (McDonald and Rosbash 2001;Duffield 2003). A recent study from the Allada laboratory (Flourakis et al 2015) showed that the circadian clock regulates excitability via an Na þ leak conductance (as described above). This sodium leak current depends on the expression of nonspecific crossreacting antigen (NCA) localization factor 1.…”

Section: How the Molecular Clockwork Regulates Neural Activity?mentioning

confidence: 99%

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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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Section: Daily Depolarizationmentioning

confidence: 91%

Section: How the Molecular Clockwork Regulates Neural Activity?mentioning

confidence: 99%

Membrane Currents, Gene Expression, and Circadian Clocks

Allen

Nitabach

Colwell

2017

Cold Spring Harb Perspect Biol

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“…Contributing to this rhythm is a sodium leak current mediated by NA that recently has been shown to depolarize Drosophila clock neurons (22 push the neurons into the more depolarized daytime state, eliminating the acute day/night differences in all cases ( Fig. 2 and Table S3).…”

Section: Mp (Mv)mentioning

confidence: 99%

“…Membrane potential is important for control of circadian behavior, and manipulation of Shaw and the Narrow Abdomen (NA) channels, both of which are expressed and function within clock neurons influence neuronal electrical activity, the circadian clock, and clockcontrolled behavior in both flies (20)(21)(22) and mice (23)(24)(25). The firing rate is a key component in mammalian circadian rhythmicity and can be regulated by regional and circadian expression of the sodium potassium chloride cotransporter NKCC, which switches the effects of GABA from inhibitory to excitatory across the day (26,27).…”

mentioning

confidence: 99%

Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability

Buhl

Bradlaugh

Ogueta

et al. 2016

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

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We have characterized a light-input pathway regulating Drosophila clock neuron excitability. The molecular clock drives rhythmic electrical excitability of clock neurons, and we show that the recently discovered light-input factor Quasimodo (Qsm) regulates this variation, presumably via an Na A ll organisms are subject to predictable but drastic daily environmental changes caused by the earth's rotation around the sun. It is critical for the fitness and well-being of an individual to anticipate these changes, and this anticipation is done by circadian timekeeping systems (clocks). These regulate changes in behavior, physiology, and metabolism to ensure they occur at certain times during the day, thereby adapting the organism to its environment (1). The circadian system consists of three elements: the circadian clock to keep time, inputs that allow entrainment, and outputs that influence physiology and behavior (2). Like a normal clock, circadian clocks run at a steady pace (24 h) and can be reset. In nature this environmental synchronization is done via daily light and temperature cycles, food intake, and social interactions (3).In Drosophila the central clock comprises 75 neuron pairs grouped into identifiable clusters that subserve different circadian functions (Fig. 1A). The molecular basis of the circadian clock is remarkably conserved from Drosophila to mammals (4). This intracellular molecular clock drives clock neurons to express circadian rhythms in electrical excitability, including variation in membrane potential and spike firing. Clock neurons are depolarized and fire more during the day than at night, and circadian changes in the expression of clock-controlled genes encoding membrane proteins such as ion channels and transporters likely contribute to these rhythms (5-8). Such cyclical variations in activity play a critical role in synchronizing different clock neurons and conveying circadian signals to other parts of the nervous system and body (9, 10). Furthermore, they provide positive feedback to the molecular clock, which can dampen rapidly without such feedback (7,11,12).Light resets the circadian clock every morning to synchronize the clock to the environment via Timeless (Tim) degradation after activation of the blue-light photoreceptor Cryptochrome (Cry), Quasimodo (Qsm), and potentially also visual photoreceptors (13-17). Qsm acts either independently or downstream of Cry and also is able to affect clock protein stability in Qsmnegative neurons by an unknown non-cell-autonomous mechanism (16). Recently Cry has been shown to regulate clock neuron excitability via the redox sensor of the Hyperkinetic voltage-gated potassium (K V )-β subunit (Hk) (18,19), and here we ask if Qsm affects the clock neurons in a similar way.Membrane potential is important for control of circadian behavior, and manipulation of Shaw and the Narrow Abdomen (NA) channels, both of which are expressed and function within clock neurons influence neuronal electrical activity, the circadian clock, and clockcontrolled behavi...

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“…Blue-lightactivated CRY couples to membrane depolarization in Drosophila LNv neurons by a redox-based mechanism involving potassium channel heteromultimeric complexes, consisting of the downstream redox sensor cytoplasmic potassium beta (Kvβ), HYPERKINETIC (HK), and ion-conducting voltage-gated potassium alpha (Kvα) ether-a-go-go family subunits (8). Electrical activity in the LNvs contributes to circadian rhythms (9)(10)(11), and, reciprocally, LNv neuronal firing rate is circadian-regulated (1,2,12). Circadian regulation of firing rate is widely conserved in other invertebrate and vertebrate species (13,14).…”

mentioning

confidence: 99%

CRYPTOCHROME mediates behavioral executive choice in response to UV light

Baik

Fogle

Roberts

et al. 2017

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

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Drosophila melanogaster CRYPTOCHROME (CRY) mediates behavioral and electrophysiological responses to blue light coded by circadian and arousal neurons. However, spectroscopic and biochemical assays of heterologously expressed CRY suggest that CRY may mediate functional responses to UV-A (ultraviolet A) light as well. To determine the relative contributions of distinct phototransduction systems, we tested mutants lacking CRY and mutants with disrupted opsin-based phototransduction for behavioral and electrophysiological responses to UV light. CRY and opsin-based external photoreceptor systems cooperate for UV light-evoked acute responses. CRY mediates behavioral avoidance responses related to executive choice, consistent with its expression in central brain neurons.cryptochrome | phototransduction | UV | neural decision making | Drosophila

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A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability

Cited by 193 publications

References 63 publications

Membrane Currents, Gene Expression, and Circadian Clocks

Membrane Currents, Gene Expression, and Circadian Clocks

Quasimodo mediates daily and acute light effects on Drosophila clock neuron excitability

CRYPTOCHROME mediates behavioral executive choice in response to UV light

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