About 34% of drugs approved by the FDA target a family of cell membrane proteins called G protein-coupled receptors (GPCRs). These proteins are used by cells to convert extracellular signals into intracellular responses, including responses to hormones, neurotransmitters, other outside stimuli.
The second largest subfamily of these proteins, called adhesion GPCRs (aGPCRs), are involved in numerous physiological processes in humans and other animals and have been linked to many diseases, including neurodevelopmental disorders, deafness, male infertility, schizophrenia, immune disorders, and cancers. They can bind to multiple types of proteins on neighboring cells or in the extracellular matrix, which makes them an attractive target for regulating the function of receptors or downstream signaling as cells communicate with each other. However, scientists have found it difficult so far to tweak the functions of specific aGPCRs without affecting other functions or receptors nearby.
In a new study published in Nature Communications, researchers at the University of Chicago developed a set of synthetic antibodies that target one aGPCR called Latrophilin 3, which is involved in embryogenesis, tissue development, and synapse formation. One of the antibodies works as an agonist, activating signals from Latrophilin 3 but not signals from an alternate isoform called Latrophilin 1. The antibodies can also break the interaction of Latrophilin 3 with one endogenous ligand (teneurin) while maintaining interaction with another (FLRT).
“It was surprising that the antibody did not activate the Latrophilin 1 isoform, even though it binds to both isoforms with similar affinity,” said Szymon Kordon, a graduate student in Biochemistry and Molecular Biophysics in the lab of Demet Araç at UChicago, and the first author of the study. “We provide an example that antibody-mediated modulation of receptor signaling can be unique for different isoforms and different signaling pathways.”
Now, the research will enable more studies on aGPCR function. By providing principles for fine-tuned modulation of aGPCR signaling and downstream biological functions, it establishes a foundation for development of more drug treatments that target these important proteins.
