Glucagon and the Glucagon Receptor: Merrifield Years at the Interface of Chemistry and Biology

• Published in: International journal of peptide research and therapeutics 2007-06, Vol.13 (1-2), p.19-27
• Main Author: Unson, Cecilia G
• Format: Article
• Language: English
• Subjects: Antagonists; Binding sites; Diabetes; Diabetes mellitus; Glucagon; Insulin; Peptides; Proteins; Site-directed mutagenesis; Structure-function relationships
• ISSN: 1573-3149; 1573-3904
• DOI: 10.1007/s10989-007-9082-3

The glucagon signaling system is a good model to investigate the chemical and structural requirements that dictate the interaction between a peptide hormone and its membrane-bound receptor and the cascade of events that lead to a physiological response. Secreted by pancreatic A cells, the primary target organ of glucagon is the liver where, together with insulin, it plays a central role in the maintenance of normal circulating glucose levels critical to the survival of the organism. The impetus for studying how glucagon interacts with its receptor is to gain insight into the mechanism of glucagon action in normal physiology as well as in diabetes mellitus. The principal approach towards this goal is to design and synthesize analogues of glucagon that will bind with high affinity to the glucagon receptor but will not activate it. These peptide analogues are expected to be potent antagonists of the hormone and will provide insight into the role of glucagon in diabetes. A second complementary approach is to investigate structure-function relationships in the glucagon receptor by site-directed mutagenesis and the biochemical and pharmacological characterization of mutant receptors. These studies will provide information about the peptide-binding site in the receptor and the residues that dictate ligand selectivity. A stable mammalian cell line that expresses human glucagon receptor at high-levels has been developed and should provide receptor protein for structural studies. An interdisciplinary approach combining chemical synthesis, molecular biology and biophysical methods is crucial for the conception of three-dimensional receptor models to be used in the rational design of glucagon antagonists for the management of diabetes.