Journal article
The Unique Dopamine/Ecdysteroid Receptor Modulates Ethanol-Induced Sedation in Drosophila
The Journal of neuroscience, Vol.36(16), pp.4647-4657
04/20/2016
DOI: 10.1523/jneurosci.3774-15.2016
PMCID: PMC4837687
PMID: 27098705
Abstract
Steroids profoundly influence behavioral responses to alcohol by activating canonical nuclear hormone receptors and exerting allosteric effects on ion channels. Accumulating evidence has demonstrated that steroids can also trigger biological effects by directly binding G-protein-coupled receptors (GPCRs), yet physiological roles of such unconventional steroid signaling in controlling alcohol-induced behaviors remain unclear. The dopamine/ecdysteroid receptor (DopEcR) is a GPCR that mediates nongenomic actions of ecdysteroids, the major steroid hormones in insects. Here, we report that Drosophila DopEcR plays a critical role in ethanol-induced sedation.DopEcR mutants took longer than control flies to become sedated during exposure to ethanol, despite having normal ethanol absorption or metabolism. RNAi-mediated knockdown of DopEcR expression revealed that this receptor is necessary after eclosion, and is required in particular neuronal subsets, including cholinergic and peptidergic neurons, to mediate this behavior. Additionally, flies ubiquitously overexpressing DopEcR cDNA had a tendency to become sedated quickly upon ethanol exposure. These results indicate that neuronal subset-specific expression of DopEcR in adults is required for normal sedation upon exposure to ethanol. We also obtained evidence indicating that DopEcR may promote ethanol sedation by suppressing epidermal growth factor receptor/extracellular signal-regulated kinase signaling. Last, genetic and pharmacological analyses suggested that in adult flies ecdysone may serve as an inverse agonist of DopEcR and suppress the sedation-promoting activity of DopEcR in the context of ethanol exposure. Our findings provide the first evidence for the involvement of nongenomic G-protein-coupled steroid receptors in the response to alcohol, and shed new light on the potential roles of steroids in alcohol-use disorders.
Alcohol abuse is an alarming personal and societal burden. The improvement of prevention and treatment strategies for alcohol-use disorders requires a better understanding of their biological basis. Steroid hormones profoundly affect alcohol-induced behaviors, but the contribution of their unconventional, nongenomic actions during these responses has not yet been elucidated. We found that Drosophila DopEcR, a unique G-protein-coupled receptor (GPCR) with dual specificity for dopamine and steroids, mediates noncanonical steroid actions to promote ethanol-induced sedation. Because steroid signaling and the behavioral response to alcohol are evolutionarily well conserved, our findings suggest that analogous mammalian receptors likely play important roles in alcohol-use disorders. Our work provides a foundation for further characterizing the function and mechanisms of action of nonclassical steroid GPCR signaling.
Details
- Title: Subtitle
- The Unique Dopamine/Ecdysteroid Receptor Modulates Ethanol-Induced Sedation in Drosophila
- Creators
- Emily Petruccelli - Interdisciplinary Program in Genetics, Graduate CollegeQi Li - Peking University School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing 100871, ChinaYi Rao - Peking University School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Beijing 100871, ChinaToshihiro Kitamoto - Interdisciplinary Program in Genetics, Graduate College, Department of Anesthesia, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, and toshi-kitamoto@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.36(16), pp.4647-4657
- Publisher
- United States
- DOI
- 10.1523/jneurosci.3774-15.2016
- PMID
- 27098705
- PMCID
- PMC4837687
- ISSN
- 1529-2401
- eISSN
- 1529-2401
- Grant note
- R03 AA021968 / NIAAA NIH HHS T32 NS045549 / NINDS NIH HHS F31 AA021625 / NIAAA NIH HHS T32NS045549 / NINDS NIH HHS R03AA021968 / NIAAA NIH HHS F31AA021625 / NIAAA NIH HHS
- Language
- English
- Date published
- 04/20/2016
- Academic Unit
- Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9984006356202771
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