Physiological and Pathophysiological Roles of Prostanoids; Lessons from Receptor-Knockout Mice for Clinical Applications

摘要

Prostanoids including prostaglandins (PGs) and thromboxanes (TXs) exert their actions by acting on eight types and subtypes of prostanoid receptors [1 ]. They are the PGD receptor, DP; four subtypes of PGE receptors: EP_1 EP_2, EP3; and EP_4; the PGF receptor, FP; the PGI receptor, IP; and the TXAreceptor, TP. These receptors are encoded by different genes, and all of them are rhodopsin-type, G-protein-coupled receptors with seven transmembrane domains. Dependent on changes in intracellular second messengers, these receptors can be grouped into three. One group consists of TP, FP, and EP_1 which couple to a rise in intracellular free calcium ion. The second group includes DP, EP_2, EP_4, and IP, which induce a rise in cAMP in cells. The last receptor, EP3, couples to a decrease in cAMP level. These prostanoid receptors are not distributed ubiquitously and evenly in the body; each receptor has its own unique distribution pattern. They are also subject to induction or suppression in response to various physiological and pathophysiological stimuli. A variety of physiological actions of prostanoids are thus exerted by a molecular diversity of prostanoid receptors mediating different signal transductions in the cell and distributed characteristically in the body. It is, however, not necessarily clear which type of prostanoid receptors is responsible for a prostanoid action in a particular process. Neither it is known how much prostanoids contribute to various physiological and pathophysiological processes. To address these issues, we have individually disrupted genes for all eight types of prostanoid receptors, and analyzed mice deficient in each receptor in various pathological contexts. This article summarizes our analyses on the roles of prostanoids and their receptors in pain transmission, fever generation, and allergic asthma. Development of new PG analogs based on the cloned receptors are also discussed in conjunction of knockout mice studies.