Characterization of Functional Interaction of Carboxylic Acid Group of Agonists and Arginine of the Seventh Transmembrane Domains of Four Prostaglandin E Receptor Subtypes

Abstract

Prostaglandin (PG) E₂ binds to four PGE receptor subtypes, EP1, EP2, EP3 and EP4, and induces a variety of functions through the interaction of carboxylic acid of PGE₂ and Arg residue in the seventh transmembrane domain of the receptor. To assess the role of the interaction of the carboxylic acid group of agonists and the Arg residue, which can form both ionic bonding and hydrogen bonding as a hydrogen donor, we examined the agonist activities of three types of agonist, PGE₂ with a negatively charged carboxylic acid, PHE₂ methylester, which is a hydrogen acceptor, and 1-OH PGE₂, which can accept as well as donate hydrogen but prefers to donate hydrogen rather than accept it, for four PGE receptor subtypes. Although PGE₂ methylester had slightly lower agonist activities than PGE₂ for EP1 and EP4 receptors, PGE₂ and its methylester showed the same agonist activities for EP2 and EP3 receptors, indicating that PGE₂ methylester is a potent agonist for all of the four subtypes. In contrast, 1-OH PGE₂ was a very weak agonist for all receptors. These findings demonstrate that the hydrogen bonding interaction of agonists and the Arg residue is generally sufficient for the functional activation of all of the PGE receptor subtypes.