The Reaction of Glucagon with Its Receptor: Evidence for Discrete Regions of Activity and Binding in the Glucagon Molecule

Publisher Website
Google Scholar
Abstract
Des-histidine-glucagon (DH-glucagon, glucagon 2-29 ) does not activate the glucagon-sensitive adenylate cyclase system present in either liver plasma membranes or in fat-cell “ghosts”, but inhibits the response of these systems to submaximal concentrations of glucagon. DH-glucagon also inhibits, competitively, the binding of [ 125 I]glucagon to its receptor in liver plasma membranes. Amino-terminal fragments of glucagon (glucagon 1-21 , glucagon 1-23 ) and carboxy-terminal fragments (glucagon 20-29 , glucagon 22-29 ) failed to activate adenylate cyclase, to inhibit the response of the enzyme to glucagon, or to compete with labeled glucagon at its receptor. It is concluded that the amino-terminal histidine residue of glucagon is essential for biological activity and that a hydrophobic near-carboxy-terminal region (residues 22-27) is essential for binding of glucagon to its receptor. Amino-terminal histidine may also contribute to the binding of glucagon, since the apparent affinity of DH-glucagon for the receptor is only about one-sixth that of glucagon. Thus, essentially the entire molecule of glucagon must be considered to be the biologically active species. Because, as shown elsewhere, the binding of glucagon to its receptor shows characteristics of hydrophobic bonding, and because certain detergents induce conformational changes in the carboxy-terminal binding region of glucagon, the binding is probably of a lipophilic type.