Case Number 104062 - Glucocorticoid Induced Receptor: A novel Neuropeptide Y “Y2-like” GPCR as a target for obesity
Contact: Ellen Monson
Description: The glucocorticoid-induced receptor (GIR) is an orphan G protein-coupled receptor. GIR was originally identified as a stress-responsive element from the murine T-cell line WEHI-7TG and normal thymocytes treated with glucocorticoids and forskolin. The mouse and rat GIR genes show high levels of expression in the brain. GIR mRNA distribution in the rat indicates a potential role of this receptor in the control of feeding and ingestive behavior, regulation of stress and emotional behavior, learning and memory. The human GIR gene (87% identical to rodent) also shows high levels of expression in the brain.
Rat GIR exhibits highest sequence similarity to the Neuropeptide Y (NPY)-Y2 receptor (38% identity). In experiments to characterize the pharmacology of rGIR, Dr. Randy Sallee and colleagues at the University of Cincinnati, showed that NPY-Y2 selective antagonists and agonists bind to and activate rGIR in a manner similar to NPY-Y2. However, the binding profiles of NPY and Y2 selective ligands to rGIR are distinct from NPY-Y2 receptor suggesting that GIR may represent a novel neuropeptide receptor that interacts with NPY analogs. Indeed, a novel amino acid peptide, the structure of which was modeled on the Neuropeptide Y (NPY) C-terminus, binds with nM affinity to the rGIR receptor but does not bind to any known NPY receptors.Administration of this novel peptide i.c.v. to rats results in feeding inhibition.
Based on a) its distribution in feeding regulatory areas in the forebrain and brain stem, b) its interaction with compounds such as PYY3-36 and other anorectic peptides that regulate feeding, and c) its regulation by leptin, it is likely that GIR represents a novel target for the identification of potential obesity therapeutics.Dr. Sallee’s group has identified small molecule antagonists and agonists of GIR that are currently being tested in animals. These molecules can serve as the basis for the further development of novel GIR antagonists as potential appetite suppressants for the treatment of obesity.