GPR123 Activation by Steroid Ligands

Project Summary Steroid hormones mediate crucially important aspects of development, metabolism, inflammation, immune function, and behavior. Many effects of steroids are due to activation of their classical nuclear receptors to control transcription, but steroids can also control numerous cellular processes via rapid stimulation of G protein signaling. For most steroids, though, the receptors mediating these rapid non-genomic actions have not yet been identified. In preliminary studies, the adhesion G protein-coupled receptor GPR123 (also known as ADGRA1), which is highly expressed in the brain and known to regulate metabolism, was screened for potential stimulation by steroids and several hits were identified. We propose to build on these screens and pharmacologically characterize steroid binding by GPR123, including assessment of signaling bias by steroid ligands through both G protein- and arrestin-mediated signaling pathways. We also propose to elucidate the structural determinants of steroid activation of GPR123. These studies will provide new insights into the rapid non-genomic actions of steroid hormones and furthermore lay the groundwork for the development of GPR123- targeted therapeutics that might be useful in the treatment of metabolic disorders and other human diseases.