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Family B Seven Transmembrane G Protein-Coupled Receptors - Ligand Binding Model of the Glucagon and Glucagon-Like Peptide-1 Receptors

Steffen Runge

Glucagon and the glucagon-like peptide-1 (GLP-1) are homologous peptide hormones with regulatory functions in glucose homeostasis and they mediate their physiological effects via likewise homologous integral membrane proteins that belong to family B of the seven transmembrane (7TM) G protein-coupled receptors (GPCRs). Glucagon increases hepatic glucose production via the hepatic glucagon receptor and GLP-1 potentiates the glucose-dependent insulin secretion of the pancreatic islets via the pancreatic GLP-1 receptor. Reduction of unrestrained hepatic glucose production and enhancement of pancreatic insulin secretion are principal goals in treatment of patients with type 2 diabetes. Therefore inhibition of the hepatic glucagon receptor and activation of the pancreatic GLP-1 receptor are potential therapeutic approaches for type 2 diabetes.

Specificity of ligand-receptor pairs has developed during evolution to ensure distinct physiological functions. The glucagon and GLP-1 receptors selectively recognize glucagon and GLP-1, respectively, but the molecular basis of ligand binding and selectivity is not known. The objective of this Ph.D.project was to increase the knowledge about ligand binding by identification of molecular determinants of ligand-receptor specificity. A combined analysis of chimeric ligands and chimeric receptors was applied and the results showed that the amino-terminal extracellular domain defined almost completely the glucagon/GLP-1 selectivity profile of the GLP-1 receptor by selective interaction with the GLP-1 carboxy-terminus. The 7TM region and connecting loops (the core domain) of the GLP-1 receptor was activated potently and effectively by both the glucagon and GLP-1 amino-terminals and does not contribute significantly to the glucagon/GLP-1 selectivity profile of the GLP-1 receptor. The glucagon/GLP-1 selectivity profile of the glucagon receptor was explained by selective recognition of both the glucagon C-terminus by the N-terminal extracellular domain and the glucagon N-terminus by the core domain.

The glucagon/GLP-1 selectivity profile of the glucagon receptor core domain encouraged a search for selectivity determinants that determined specificity for the glucagon N-terminus. Dissection of the glucagon receptor core domain identified three distinct epitopes that determined specificity for three different residues of the glucagon amino-terminus. The results provide three constraints that orientate the glucagon N-terminus with respect to the structural elements of the glucagon receptor core domain. The conclusions are summarized in a binding model that accounts for the ligand selectivity of the glucagon and GLP-1 receptors.

This thesis reviews briefly the biological functions of glucagon and GLP-1 and reviews more extensively the structure, ligand binding and functional properties of family B 7TM GPCRs, with special emphasis on the glucagon and GLP-1 receptors. The review integrates a discussion of the main results obtained during this Ph.D. project and the reader is referred to the attached articles for detailed descriptions.

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