Ethanol Tolerance Caused by <i>slowpoke</i> Induction in <i>Drosophila</i>

Cowmeadow, Roshani B.; Krishnan, Harish R.; Ghezzi, Alfredo; Al-Hasan, Yazan; Wang, Yan. Z.; Atkinson, Nigel S.

doi:10.1111/j.1530-0277.2006.00087.x

Cited by 88 publications

(120 citation statements)

References 40 publications

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“…When exposed to alcohol, flies initially become hyperactive, but soon lose postural control and fall through the inebriometer at a rate that is correlated with their sensitivity. Following recovery, a second exposure reveals the development of tolerance reflected in a longer knockdown time (Moore et al 1998;Scholz et al 2000;Singh and Heberlein 2000;Cowmeadow et al 2005Cowmeadow et al , 2006Scholz et al 2005;Wen et al 2005;Morozova et al 2006Morozova et al , 2009Kong et al 2009). …”

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confidence: 99%

Transcriptional Networks for Alcohol Sensitivity in Drosophila melanogaster

2011

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Understanding the genetic architecture of polygenic traits requires investigating how complex networks of interacting molecules mediate the effect of genetic variation on organismal phenotypes. We used a combination of P-element mutagenesis and analysis of natural variation in gene expression to predict transcriptional networks that underlie alcohol sensitivity in Drosophila melanogaster. We identified 139 unique P-element mutations (124 in genes) that affect sensitivity or resistance to alcohol exposure. Further analyses of nine of the lines showed that the P-elements affected expression levels of the tagged genes, and P-element excision resulted in phenotypic reversion. The majority of the mutations were in computationally predicted genes or genes with unexpected effects on alcohol phenotypes. Therefore we sought to understand the biological relationships among 21 of these genes by leveraging genetic correlations among genetically variable transcripts in wild-derived inbred lines to predict coregulated transcriptional networks. A total of 32 ''hub'' genes were common to two or more networks associated with the focal genes. We used RNAi-mediated inhibition of expression of focal genes and of hub genes connected to them in the network to confirm their effects on alcohol-related phenotypes. We then expanded the computational networks using the hub genes as foci and again validated network predictions. Iteration of this approach allows a stepwise expansion of the network with simultaneous functional validation. Although coregulated transcriptional networks do not provide information about causal relationships among their constituent transcripts, they provide a framework for subsequent functional studies on the genetic basis of alcohol sensitivity.

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confidence: 99%

Transcriptional Networks for Alcohol Sensitivity in Drosophila melanogaster

2011

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“…In the Drosophila nervous system a null mutation of the slowpoke gene completely eliminated rapid tolerance to ethanol (Cowmeadow et al 2005). Ethanol increased slowpoke expression in the nervous system coincident with the induction of ethanol tolerance (Cowmeadow et al, 2006). Since an increase of slowpoke expression is also caused by cold, by CO 2 sedation (Ghezzi et al, 2010) or by heat-shock promoters (Cowmeadow et al, 2006) it was suggested that this is a more common mechanism for acquisition of tolerance.…”

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

“…Ethanol increased slowpoke expression in the nervous system coincident with the induction of ethanol tolerance (Cowmeadow et al, 2006). Since an increase of slowpoke expression is also caused by cold, by CO 2 sedation (Ghezzi et al, 2010) or by heat-shock promoters (Cowmeadow et al, 2006) it was suggested that this is a more common mechanism for acquisition of tolerance. Interestingly the Drosophila slowpoke gene appears to contain a binding site for CREB (cyclic-AMP response element binding protein) which has been implicated in learning and memory and hence may also be involved in the ethanol response (Cowmeadow et al, 2006) and possibly in the memory deficits after excessive alcohol intake.…”

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

“…Since an increase of slowpoke expression is also caused by cold, by CO 2 sedation (Ghezzi et al, 2010) or by heat-shock promoters (Cowmeadow et al, 2006) it was suggested that this is a more common mechanism for acquisition of tolerance. Interestingly the Drosophila slowpoke gene appears to contain a binding site for CREB (cyclic-AMP response element binding protein) which has been implicated in learning and memory and hence may also be involved in the ethanol response (Cowmeadow et al, 2006) and possibly in the memory deficits after excessive alcohol intake. Further experimentation into the molecular mechanism of tolerance using single channel recoding revealed that only after expression of the somatic BK -subunit together with the brain specific 4-subunit ethanol dosedependently increased the open probability of channels and decreased the duration of action potentials whereas BK -subunit together with the ß1-subunit expressed in dendrites was insensitive to ethanol Martin et al, 2008) Human BK channels (hslo) are also potentiated by alcohol being dependent on the presence of auxiliary -subunits (Feinberg-Zadek & Treistman 2007).…”

Section: Bk Channels -And Ethanol Tolerancementioning

confidence: 99%

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BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

Hermann¹,

Ситдикова²,

Weiger³

2012

Patch Clamp Technique

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“…Further open questions are the interesting connection of alcohol actions with the adenosine receptors (Dar et al, 1983;Choi et al, 2004;Dar, 2006), protein kinases (Hodge et al, 1999;Proctor et al, 2003;Wallace et al, 2007), NMDA and AMPA receptors (Lovinger et al, 1989;Woodward, 2000), BK channels (Martin et al, 2004;Cowmeadow et al, 2006), glycine receptors (Davies et al, 2003), K v + channels (Espinosa et al, 2001), and the modulation of alcohol actions via G protein-coupled receptors (Wan et al, 1996;Nie et al, 2004;Besheer et al, 2006) as well as the molecular mechanism behind of the fascinating observation of behavioral alcohol antagonism by pressure (Alkana et al, 1985;Davies and Alkana, 2001). The challenge is to find answers to these and many more important questions in the future and to integrate these findings into an increasingly comprehensive picture on which the majority of us can agree.…”

Section: Summary Open Questions and Future Developments And Apparentmentioning

confidence: 99%

GABAA receptor subtypes: the “one glass of wine” receptors

Olsen

Hanchar

Meera

et al. 2007

Alcohol

128

121

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This review discusses evidence for and apparent controversy about, GABA A receptor subtypes that mediate alcohol effects experienced during social drinking. GABA A receptors that contain the β3 and δ subunits were shown to be enhanced by alcohol concentrations that mirror the concentrationdependence of alcohol responses in humans. A mutation (α6R100Q) previously found in alcohol non-tolerant (ANT) rats in the cerebellar GABA A receptor α6 subunit is sufficient for increased alcohol-induced ataxia in rats homozygous for this mutation (α6-100QQ) and further increases alcohol-sensitivity of tonic GABA currents (mediated by α6βδ receptors) in cerebellar granule cells of α6-100QQ rats and in recombinant α6R100Qβ3δ receptors. This provided the first direct evidence that these types of receptors mediate behavioral effects of ethanol. Furthermore the behavioral alcohol antagonist Ro15-4513 specifically reverses ethanol enhancement on α4/6β3δ receptors. Unexpectedly, native and recombinant α4/6β3δ receptors bind the behavioral alcohol antagonist Ro15-4513 with high affinity and this binding is competitive with EtOH, suggesting a specific and mutually exclusive (competitive) ethanol/Ro15-4513 site which explains the puzzling activity of Ro15-4513 as a behavioral alcohol antagonist.Our conclusion from these findings is that alcohol/Ro15-4513-sensitive GABA A receptor subtypes are important alcohol targets and that alcohol at relevant concentrations is more specific than previously thought. In this review we discuss technical difficulties in expressing recombinant δ subunit-containing receptors in oocytes and mammalian cells, that may have contributed to negative results and confusion. Not only because we have reproduced detailed positive results numerous times, and we and many others have built extensively on basic findings, but also because we explain and combine many previously puzzling results into a coherent and highly plausible paradigm on how alcohol exerts an important part of its action in the brain, we are confident about our findings and conclusions. However, many important open questions remain to be answered.

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Ethanol Tolerance Caused by slowpoke Induction in Drosophila

Cited by 88 publications

References 40 publications

Transcriptional Networks for Alcohol Sensitivity in Drosophila melanogaster

Transcriptional Networks for Alcohol Sensitivity in Drosophila melanogaster

BK Channels – Focus on Polyamines, Ethanol/Acetaldehyde and Hydrogen Sulfide (H2S)

GABAA receptor subtypes: the “one glass of wine” receptors

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