<i>slo</i>
            K
            <sup>+</sup>
            channel gene regulation mediates rapid drug tolerance

Ghezzi, Alfredo; Al-Hasan, Yazan; Larios, Leo E.; Bohm, Rudolf A.; Atkinson, Nigel S.

doi:10.1073/pnas.0405584101

Cited by 53 publications

(127 citation statements)

References 32 publications

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“…slo is highly regulated at the transcriptional level, employing several alternative promoters and splice variants (29)(30)(31). To distinguish between a neuronal and/or a muscular defect associated with the strong impairment observed in slo mutants, we evaluated locomotor activity in two transgenic lines that rescue predominantly neuronal [B52H;slo 4 (32)] or muscular [M131;slo 4 (30)] defects associated with the lack of SLO. Wildtype flies entrain to light-dark (LD) cycles, consolidating their activity around the lights on/off transitions; under DD, a condition that allows the endogenous clock to manifest, flies are active throughout the subjective day, and the periodicity is usually close to, but not exactly, 24 h (Fig.…”

Section: Resultsmentioning

confidence: 99%

Impaired clock output by altered connectivity in the circadian network

Fernández

Chu

Villella

et al. 2007

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

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Substantial progress has been made in elucidating the molecular processes that impart a temporal control to physiology and behavior in most eukaryotes. In Drosophila, dorsal and ventral neuronal networks act in concert to convey rhythmicity. Recently, the hierarchical organization among the different circadian clusters has been addressed, but how molecular oscillations translate into rhythmic behavior remains unclear. The small ventral lateral neurons can synchronize certain dorsal oscillators likely through the release of pigment dispersing factor (PDF), a neuropeptide central to the control of rhythmic rest-activity cycles. In the present study, we have taken advantage of flies exhibiting a distinctive arrhythmic phenotype due to mutation of the potassium channel slowpoke (slo) to examine the relevance of specific neuronal populations involved in the circadian control of behavior. We show that altered neuronal function associated with the null mutation specifically impaired PDF accumulation in the dorsal protocerebrum and, in turn, desynchronized molecular oscillations in the dorsal clusters. However, molecular oscillations in the small ventral lateral neurons are properly running in the null mutant, indicating that slo is acting downstream of these core pacemaker cells, most likely in the output pathway. Surprisingly, disrupted PDF signaling by slo dysfunction directly affects the structure of the underlying circuit. Our observations demonstrate that subtle structural changes within the circadian network are responsible for behavioral arrhythmicity.circadian circuitry ͉ Drosophila ͉ pigment dispersing factor ͉ potassium channels ͉ slowpoke R hythmicity in rest-activity cycles in Drosophila is under control of the circadian clock, which is based on selfsustaining, cell-autonomous transcriptional negative feedback loops. These feedback loops ultimately give rise to rhythms in the abundance, phosphorylation state, and nuclear localization of key intracellular proteins, such as period (PER) and timeless (TIM) (1). To date, several neuronal clusters have been shown to include a molecular oscillator. The one best understood encompasses the small ventral lateral neurons (LNvs), comprised of five cells, of which four rhythmically release the neuropeptide pigment dispersing factor (PDF) at their dorsal terminals. Other oscillators within the fly brain include the dorsal lateral neurons (LNds) together with the dorsal neurons (DN1-3) (2). Ablation of all LNvs by overexpression of proapoptotic genes, as well as null mutations on the pdf gene or its receptor, cause behavioral arrhythmicity a few days upon transfer to constant conditions (3-6) likely through the gradual loss of synchronization among the components of the small LNv cluster (7).The question of how the intracellular molecular oscillations taking place within specific neuronal clusters ultimately drive rhythmic locomotor activity has only recently been approached in Drosophila (7-11). Molecular oscillations must be somehow transduced into neuronal function to...

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Section: Resultsmentioning

confidence: 99%

Impaired clock output by altered connectivity in the circadian network

Fernández

Chu

Villella

et al. 2007

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

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“…This channel responds both to increases in free Ca 2+ and to changes in membrane potential and is thus believed to play a major role in shaping neuronal excitability and regulating synaptic transmission (8). Because of its central role as a regulator of excitability of nerve terminals, we have proposed that this channel is a likely contributor to the homeostatic mechanism that resists unfavorable changes in net cellular excitability and mediates tolerance to sedation (5). Here, we electrophysiologically test whether drug-induced slo expression acts as a neural excitant that could directly counter the depressant effects of the drug and if, after drug clearance, the change in slo expression generates a symptom of drug withdrawal.…”

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confidence: 99%

“…In these experiments, previously treated flies recover from sedation and resume normal behavior significantly earlier than naive flies. Transcription from the slo gene was shown to be both sufficient and necessary for the development of tolerance to the behavioral effects of benzyl alcohol, as a mutation that eliminates slo expression prevents tolerance, and expression from an inducible slo transgene mimics tolerance in naive animals (5,6).…”

mentioning

confidence: 99%

BK channels play a counter-adaptive role in drug tolerance and dependence

Ghezzi¹,

Pohl²,

Wang³

et al. 2010

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

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Disturbance of neural activity by sedative drugs has been proposed to trigger a homeostatic response that resists unfavorable changes in net cellular excitability, leading to tolerance and dependence. The Drosophila slo gene encodes a BK-type Ca 2+ -activated K + channel implicated in functional tolerance to alcohol and volatile anesthetics. We hypothesized that increased expression of BK channels induced by these drugs constitutes the homeostatic adaptation conferring resistance to sedative drugs. In contrast to the dogmatic view that BK channels act as neural depressants, we show that drug-induced slo expression enhances excitability by reducing the neuronal refractory period. Although this neuroadaptation directly counters some effects of anesthetics, it also causes long-lasting enhancement of seizure susceptibility, a common symptom of drug withdrawal. These data provide a possible mechanism for the long-standing counter-adaptive theory for drug tolerance in which homeostatic adaptations triggered by drug exposure to produce drug tolerance become counter-adaptive after drug clearance and result in symptoms of dependence.addiction | anesthesia | drug abuse | seizure | epilepsy

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“…Ethanol and other drugs such as benzyl alcohol, a common sedative, induces neural expression of the slo gene and the production of rapid tolerance (Cowmeadow et al 2005;Ghezzi et al, 2004). The drugs increased expression of the slo gene, enhanced neuronal excitation by reducing the refractory period between action potentials and augmented seizure susceptibility (Ghezzi et al, 2010).…”

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%