Identification of novel GLP-1 receptor interacting proteins

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G protein-coupled receptors (GPCRs) are one of the body's largest class of proteins, being expressed in virtually every mammalian cell. In cells they are the receivers of chemical signals from other cells, and act as conduits for cell to cell communication and cellular responses. There are currently 5 subclasses of GPCRs, including the B-class receptors, which include the Glucagon-like peptide 1 receptor (GLP1R). GLP-1 receptors are are best known for being expressed in pancreatic beta-cells that make and secrete insulin and in cells in the brain that regulate appetite. In the beta-cell and in the brain, the chemical signal for the receptor is the hormone GLP-1. GLP-1 is primarily released during feeding and travels to the beta-cell from the intestine to stimulate insulin secretion, which lowers blood sugar. In the brain, GLP-1 causes a feeling of fullness, to slow or inhibit further feeding. What is currently not well understood for the GLP1R and for that matter most GPCRs, is how a chemical signal and its receptor cause the cell to take action, like to secrete insulin. That is precisely the purpose of this grant. The overall goal of the present proposal is to employ in living cells a novel protein binding assay developed to identify and functionally characterize proteins that directly interact with and modulate GPCR activity, using the GLP1R as our model system. Importantly, we provide substantial preliminary data that the GLP1R in the brain interacts with a new group of proteins directly and that this interaction, depending on the protein, amplifies or dampens the cellular response. We now wish to use this same strategy to find proteins (specifically in the pancreatic beta cell) that function to transduce the GLP1 signal to insulin secretion. Once these proteins are identified, we will systematically determine how they interact with the GLP1R and how this interaction changes insulin secretion. We are specifically looking for proteins that when they interact with GLP1R, stimulate insulin release because they may serve as an exciting new way to stimulate insulin secretion.