Structural and Functional Studies of Adhesion GPCRs in the Central Nervous System
The G-protein coupled receptor superfamily is the most commonly targeted group of molecules for the treatment of human diseases. Adhesion-type GPCRs are a newly discovered GPCR family with emerging roles in multiple brain functions and disorders such as brain development, synapse function, neurodevelopmental disorders, attention deficit hyperactivity disorder, and cancers of the brain. The treatments for these diseases are hampered because of insufficient basic information about adhesion GPCRs. The goal of this proposal is to understand the mechanism by which adhesion GPCRs function in the brain, and to decipher the role of the newly discovered GAIN domain in their function. I aim to identify ligands for adhesion GPCRs and to reveal the molecular mechanisms by which adhesion GPCRs recognize their ligands through their GAIN domains. I also aim to shed light on how the extracellular GAIN domain and the membrane-embedded transmembrane helices act together to regulate receptor activity. My results will have an enormous impact scientifically by elucidating how cellular adhesion couples to intracellular signaling in multicellular organisms, a key phenomenon that is disrupted in many brain diseases, and, translationally, through targeted drug design to treat brain diseases caused by malfunctioning adhesion GPCRs.