Abstract
Prostaglandin (PG) E(2) exerts its actions by acting on a group of G-protein-coupled receptors (GPCRs). There are four GPCRs responding to PGE(2) designated subtypes EP1, EP2, EP3, and EP4 and multiple splicing isoforms of the subtype EP3. The EP subtypes exhibit differences in signal transduction, tissue localization, and regulation of expression. This molecular and biochemical heterogeneity of PGE receptors leads to PGE(2) being the most versatile prostanoid. Studies on knock-out mice deficient in each EP subtype have defined PGE(2) actions mediated by each subtype and identified the role each EP subtype plays in various physiological and pathophysiological responses. Here we review recent advances in PGE receptor research.
Highlights
Prostaglandin (PG) E2 exerts its actions by acting on a group of G-protein-coupled receptors (GPCRs)
Receptors mediating prostanoid actions were characterized first by pharmacological analysis, which indicated the presence of one receptor each, named DP, FP, IP, and TP, for PGs of the D, F, and I types and TXA, respectively, and four different receptors designated EP1, EP2, EP3, and EP4 for the E type PGs. Molecular identification of these receptors was achieved by their cDNA cloning, which revealed that the prostanoid receptors are G-proteincoupled receptors (GPCRs) and that there is a family of eight GPCRs that correspond to the pharmacologically defined receptors
All of the four EP subtypes respond to PGE2, the amino acid identity among the EPs is limited; the identity of EP1 to EP2, EP3, and EP4 is 30, 33, and 28%, respectively
Summary
Yukihiko Sugimoto‡ and Shuh Narumiya§1 From the ‡Department of Physiological Chemistry, Graduate School of Pharmaceutical Sciences and the §Department of Pharmacology, Faculty of Medicine, Kyoto University, Kyoto 606-8501, Japan. The EP subtypes exhibit differences in signal transduction, tissue localization, and regulation of expression This molecular and biochemical heterogeneity of PGE receptors leads to PGE2 being the most versatile prostanoid. Prostanoids including various prostaglandins (PGs) and thromboxanes (TXs) are cyclooxygenase (COX) metabolites of C20-unsaturated fatty acids such as arachidonic acid These substances are synthesized in response to various stimuli in a variety of cells, released immediately after synthesis, and act in the vicinity of their synthesis to maintain local homeostasis [1]. A recent study revealed the presence of the ninth prostanoid receptor that belongs not to the prostanoid receptor family described above but to the chemoattractant receptor family [4] This receptor called CRTH2 or DP2 is expressed in Th2 cells and eosinophils and mediates some of the PGD2 actions on these cells such as chemotaxis. The cloned EP subtypes have been used in the development of compounds specific to each subtype
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