This application addresses the structural features of the GLP-1 receptor and the ligands GLP-1 and GLP-2 which activate this receptor which in turn leads to cAMP elevations. This receptor system is important in glucose regulation due to its function to promote insulin secretion in pancreatic beta cells and to inhibit glucagon secretion and to delay gastric emptying. The applicant will define residues in the GLP-1 receptor that alter its ability to respond to ligand and its ability to link to G protein function and cAMP regulation. He has made interesting observations relating to these goals, in particular the discovery that there are species differences in GLP-2 binding to GLP-1 receptor from rat vs. human. Preliminary data are presented related to these findings that form the basis of many of the experiments in Aims 1 and 2. These proposed experiments are designed to refine our understanding of the specific residues in both the ligands and the GLP-1 receptor that are key to receptor function, which may lead to the identification of agonists and antagonists that are superior to those now known. Another direction that the experiments will take(Aim 3) is the evaluation of the hypothesis that there is a tonic activity of the GLP-1 receptor that functions in beta cells to modulate insulin secretion even in the absence of ligands. Receptor will be expressed in cell lines derived from beta cells and its ability to modulate cAMP levels in the absence of ligands evaluated.
