Project Summary G-protein coupled receptors (GPCRs) represent the single largest class of druggable targets in the human genome. Of the 390 or so druggable and non-olfactory human GPCRs there exist many which are orphan and/or understudied; we refer to these as “oGPCRs”. Here we will illuminate the pharmacology, signaling pathways, chemical biology, distribution and function of the 143 oGPCRs listed in the RFA. This project seeks to discover and develop specific, community accessible tools— chemical probe molecules and engineered animals—that enable investigators to interrogate the biological functions of oGPCRs. Given the central importance of GPCRs for all areas of biomedical research, illuminating the pharmacology, function, signaling and chemical biology of these oGPCRs will have far-reaching impact for both therapeutics and basic biomedical science.

Public Health Relevance G-protein coupled receptors respond to signals from light to adrenaline, lipids to chemokine proteins; GPCRs control physiology ranging from vision to respiration, heart rate to learning and memory and are the family of proteins most targeted by therapeutic drugs. Astonishingly, 1/3rd of the pharmacologically relevant GPCRs remain orphans, without specific reagents to control their activity. The advent of new technologies enables the development of chemical probes, genetic reporters and perturbants for the oGPCRs. This project will create novel tools suitable for illuminating the functions and ultimately public health relevance of oGPCRs that will enable new therapeutics for a wide variety of human diseases.