Steroid hormones play a critical role in various neurological and psychiatric conditions. In addition to the "genomic" mechanisms involving nuclear steroid hormone receptors, biological effects of steroids are also mediated by "nongenomic" mechanisms that occur rapidly and independently of new mRNA synthesis. The functions and molecular mechanisms for such unconventional steroid signaling, particularly in the nervous system, are still poorly understood. This gap in the knowledge base represents an important unmet need for a mechanism-based understanding of nervous system disorders related to steroid hormones. The long-term goal is to understand how steroid hormones modulate nervous system functions and thereby control behavior. The objective of this particular application is to elucidate the fundamental mechanisms for nongenomic steroid signaling that controls ethanol-induced behaviors using the fruit fly Drosophila. Recent genetic studies in the applicant's lab demonstrate that DopEcR, a G-protein coupled receptor (GPCR) for the insect steroid hormone ecdysone, plays a significant role in behavioral responses to ethanol. This new finding provides an unprecedented opportunity to investigate the underpinnings for a novel GPCR-mediated steroid signaling that is important for alcohol-induced behavior, by taking advantage of Drosophila genetics. The central hypothesis is that DopEcR is a unique dual receptor for ecdysone and dopamine, and that it modulates resistance to the sedative effects of ethanol by negatively regulating epidermal growth factor receptor (EGFR) signaling. To test this hypothesis and attain the objective of this application, we will pursue the following two specific aims: 1) Determine the expression pattern of DopEcR and sites of its actions;and 2) Identify molecular components involved in DopEcR-mediated signaling. Under the first aim, immunological and genetic methods will be used to determine the anatomical localization of DopEcR protein in the adult brain, whereas rescue and phenocopy experiments will be performed to identify brain neurons involved in DopEcR-mediated steroid actions. Under the second aim, roles of two ligands (ecdysone and dopamine) and potential downstream signaling (EGFR signaling) in DopEcR actions will be investigated using pharmacological and genetic methods. The genetic approach is innovative, because it utilizes not only a null allele, but also various genetic tools uniquely available in Drosophila to study the mechanisms responsible for nongenomic steroid signaling. The expected outcomes will form an essential foundation for understanding the novel nongenomic steroid signaling that plays critical roles in regulation of alcohol-induced behavior. This study is significant, because it is expected to provide strong mechanism-based in vivo evidence for a novel steroid signaling in the nervous system, which may ultimately contribute toward the development of innovative strategies for the prevention and treatment of alcohol use disorders as well as other common diseases that are affected by steroid hormones.
The proposed research is expected to reveal the basic mechanisms underlying a novel steroid signaling that plays critical roles in regulation of alcohol-induced behaviors. It is relevant to public health, as well as to the NIH's mission, because such information is essential to develop better therapies and preventive strategies for alcohol use disorders that constitute the highly prevalent health problem worldwide.
|Ishimoto, Hiroshi; Wang, Zhe; Rao, Yi et al. (2013) A novel role for ecdysone in Drosophila conditioned behavior: linking GPCR-mediated non-canonical steroid action to cAMP signaling in the adult brain. PLoS Genet 9:e1003843|