Molecular aspects of the structures and functions of the prostaglandin E receptors

Abstract

Prostaglandin (PG) E2 exerts a variety of biological activities for the maintenance of local homeostasis in the body. The effects of PGE₂ are exerted by a variety of PGE receptors, which are different in their signal transduction properties and are classified into four subtypes, EP1, EP2, EP3 and EP4. We have isolated the mouse cDNAs for these PGE receptors and characterized the cloned receptors. EP1, EP2, EP3 and EP4 receptors consist of 405, 362, 365 and 513 amino acid residues with a putative seven hydrophobic domains, respectively. When expressed in mammalian cells, EP1 showed elevation of intracellular [Ca²⁺], EP2 and EP4 stimulated adenylate cyclase and EP3 inhibited the enzyme. Northern blot and in situ hybridization analyses have shown that these subtypes are differently localized to specific tissues and cells. We have identified multiple isoforms of the EP3 receptor (EP3α, EP3β, and EP3γ) which differ in their carboxy-terminal domains. These isoforms displayed identical agonist binding properties, but were functionally different in the efficiency of G protein activation, the specificity of G protein coupling, and sensitivity to agonist-induced desensitization. The diverse physiological actions of PGE₂ are elicited by the molecular diversity of the receptor subtypes and isoforms distributed differently in the body.