Corticosteroids control many brain functions and behaviors, including adaptive responses to acute stress resulting from social, environmental, or physiological challenges. Some of these corticosteroid responses occur very rapidly--within seconds for changes in intracellular ions and second messengers, or within a few minutes for changes in secretions and behaviors. These responses are too rapid to be easily explained by the classic genomic model for steroid action. Instead they suggest there may be alternative, non-genomic signaling pathways. Our research in an amphibian demonstrated that a membrane receptor for corticosteroids exists in neuronal membranes. Based on pharmacological responses, the receptor appears to be in the G protein-coupled receptor (GPCR) superfamily. Opioid receptors, another member of GPCR family, also play important roles in regulating brain functions and behaviors in response to acute stress. For a number of reasons, including recent data showing that a subset of kappa-selective opioid ligands bind to the membrane corticosteroid receptor, we suggest that the membrane corticosteroid receptor is structurally related to the kappa opioid receptor and orphan opioid-like receptor. As a first step toward discovering the molecular identity of the membrane receptor for corticosteroids, this research project will conduct research on opioid-like receptors in an amphibian research model. Behavioral studies, ligand-binding assays, and molecular techniques will be used to better understand the structure and functional relationship between the membrane corticosteroid receptor and the opioid-like receptors. There are four parts to the research project: first, the binding site selectivity for corticosteroids and opioids will be characterized. Second, behavioral tests will determine the relative potencies of sufficiently selective steroids and opioids to inhibit male sexual behaviors. Third, cDNAs that encode for the opioid-like receptor proteins will be isolated and cloned. Fourth, ligand selectivity for the binding sites in transiently expressed opioid-like receptors will be characterized. These studies will provide information, for the first time in any species, about the convergence in receptor mechanisms for corticosteroids and dynorphin peptides. The studies also might reveal the molecular identity of a membrane receptor for corticosteroids.
