Genetic and Pharmacological Analysis of Prostanoid Receptor Function
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PERSPECTIVE SERIES Prostaglandins and their precursors Garret A. FitzGerald, Series Editor Genetic and pharmacological analysis of prostanoid receptor function Shuh Narumiya1 and Garret A. FitzGerald2 1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto, Japan 2Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania, USA Address correspondence to: Shuh Narumiya, Kyoto University, Faculty of Medicine, Department of Pharmacology, Yoshida, Sakyo-ku, Kyoto 606, Japan. Phone: 81-75-753-4392; Fax: 81-75-753-4693; E-mail: [email protected]. J. Clin. Invest. 108:25–30 (2001). DOI:10.1172/JCI200113455. When tissues are exposed to diverse physiological and via membrane receptors on the surface of target cells. pathological stimuli, arachidonic acid is liberated Indeed, a family of membrane receptors mediating their from membrane phospholipids and is converted to actions has been characterized and cloned, and knock- prostanoids, including the prostaglandins (PGs) and out mice deficient in each of their genes have been devel- the thromboxanes (Tx’s), by the action of cyclooxyge- oped. In addition, highly selective agonists and antago- nase (COX). The COX reaction results in the forma- nists for the cloned receptors have been developed. tion of an unstable endoperoxide intermediate, PGH2, Nuclear actions of prostanoids have also been reported which, in turn, is metabolized to PGD2, PGE2, PGF2α, and putative nuclear prostanoid receptors have been PGI2, and TxA2 by cell-specific isomerases and syn- proposed, particularly for cyclopentenone PGs. In this thases. Prostanoids thus formed are immediately article, we describe the current status of the studies on released outside of the cell, with little if any of the membrane prostanoid receptor biology and discuss the product remaining in the cell. Because they are either clinical potential of receptor-selective drugs. We then chemically or metabolically unstable, it is believed critically examine the current evidence for activation of that prostanoids work only locally, near their site of nuclear receptors by prostanoids. production. PGI2 and TxA2 spontaneously degrade into inactive compounds under physiological condi- Membrane prostanoid receptors: tions, and other PGs are enzymatically inactivated studies in knockout mice during a single passage through the lung. In addition, Eight types and subtypes of membrane prostanoid PGD2 and PGE2 are slowly dehydrated in biological receptors are conserved in mammals from mouse to fluids containing serum albumin to yield the human (2): the PGD receptor (DP), four subtypes of the cyclopentenone PGs, PGA2 and PGJ2, which contain PGE receptor (EP1, EP2, EP3, and EP4), the PGF recep- an α,β-unsaturated ketone. tor (FP), the PGI receptor (IP), and the TxA receptor Although prostanoids are generally regarded as (TP). All are G protein–coupled rhodopsin-type recep- hydrophobic compounds, they do not permeate the cell tors with seven transmembrane domains, and each is membrane freely. One PG transporter (PGT), a mem- encoded by different genes. In addition, there are sev- ber of the organic anion transporter polypeptide fami- eral splice variants of the EP3, FP, and TP receptors, ly, has been identified and is found in a limited range which differ only in their C-terminal tails. Among the of cells, where it is subject to regulation by humoral eight types and subtypes, the IP, DP, EP2, and EP4 and physical stimuli. Indeed, vascular expression of the receptors mediate a cAMP rise and have been termed PGT appears to account for clearance of most classes “relaxant” receptors, whereas the TP, FP, and EP1 recep- of PGs when these compounds are infused into an ani- tors induce calcium mobilization and constitute a mal and enter its pulmonary circulation. Indeed, PGI2, “contractile” receptor group. The remaining receptor, the only PG that is not a substrate for PGT, is also EP3, induces a decline in cAMP levels and has been unique in that it is not subject to clearance during tra- termed the “inhibitory” receptor. However, the effects versal of the pulmonary circulation. However, there is of prostanoids on these G protein–coupled signaling strong evidence that other transport systems mediate pathways may change as a function of ligand concen- the uptake of at least some prostanoids, since despite tration or structure. Thus, while PGI2 analogs ligate the the restricted expression of PGT, cyclopentenone PGs IP and activate adenylate cyclase via Gs in a dose- are efficiently transported into most cells. For more on dependent manner, higher concentrations of the ligand transport and metabolism of prostanoids, see Fitz- couple the IP to phospholipase C activation and calci- patrick and Soberman (this Perspective series, ref. 1). um mobilization (3), probably via Gq. Similarly, activa- Prostanoids, with the possible exception of the tion of the FP in cardiomyocytes by either PGF2α, its cyclopentenone PGs, are believed to exert their actions cognate ligand, or 8,12-iso-iPF2α-III, a PGF2α isomeric The Journal of Clinical Investigation | July 2001 | Volume 108 | Number 1 25 Prostaglandins and their precursors PERSPECTIVE SERIES Garret A. FitzGerald, Series Editor Table 1 drugs suppress these responses, Major phenotypes of mice deficient in prostanoid receptors and PGE2 and PGI2 can mimic these actions. Murata et al. (5) Disrupted gene Phenotypes Reference employed carrageenan-induced DP Decreased allergic responses in ovalbumin-induced bronchial asthma 8 paw swelling and acetic EP1 Decreased aberrant foci formation to azoxymethane 17 acid–induced writhing as models EP2 Impaired ovulation and fertilization 25, 26, 40 for acute inflammation and pain, Salt-sensitive hypertension 25, 26 respectively, and showed that both Vasopressor or impaired vasodepressor response to intravenous PGE2 41, 42 responses are completely absent in Loss of bronchodilation PGE2 43 IP-deficient mice. This study clear- Impaired osteoclastogenesis in vitro 14 ly demonstrated that PGI2, acting EP3 Impaired febrile response to pyrogens 7 on the IP, works as a physiological Impaired duodenal bicarbonate secretion and mucosal integrity 44 mediator of these responses. How- Enhanced vasodepressor response to intravenous infusion of PGE2 41 Disappearance of indomethacin-sensitive urine diluting function 45 ever, it remains to be seen whether EP4 Patent ductus arteriosus 46, 47 PGI2 and the IP play important roles in other types of inflamma- Impaired vasodepressor response to intravenous infusion of PGE2 41 Decreased inflammation bone resorption 12, 13 tion and pain. The profiles of FP Loss of parturition 48 prostanoids generated in an IP Thrombotic tendency 5 inflammatory site change during Decreased inflammatory swelling 5, 49 the course of inflammation and Decreased acetic acid writhing 5 are also dependent on the stimu- TP Bleeding tendency and resistance to thromboembolism 20 lus and site of inflammation (6). In pain, PGs are involved not only in hyperalgesia, an increased sensitiv- ity to a painful stimulus, but also product of lipid peroxidation, results in activation of in allodynia, a pain response to a usually nonpainful distinct, as well as overlapping, signaling pathways (4). stimulus. The latter condition is frequently seen in neu- The existence of four subtypes of the receptor for ropathic pain and is thought to occur in the spinal cord, PGE2 is remarkable, given that the other prostanoids while the former is caused by sensitizing the free end of each have only a single receptor. The homology of pain neurons in peripheral inflammation. It is interest- amino acid sequences between different types of the ing that the primary sensory neurons in the dorsal root receptors within each functional group is much high- ganglion express several types of prostanoid receptor er than that found among the four PGE receptor sub- mRNAs, including IP, EP1, EP3, and EP4 (2). The con- types. The phylogenetic tree derived from receptor tribution of receptors other than IP to pain generation homologies indicates that prostanoid receptors origi- has not been determined. nated from the primitive PGE receptor, from which the Fever and other manifestations of systemic illness. Systemic subtypes of the PGE receptor then evolved. Other PGs illness is associated with fever, adrenocorticotropic hor- and Tx receptors subsequently evolved from function- mone release, loss of appetite and libido, decreased loco- ally related PGE receptor subtypes by gene duplication. motion, and the induction of slow-wave sleep. Because This evolutionary history suggests that the different of the antipyretic action of aspirin-like drugs, it has long paralogues play distinct physiological roles. been speculated that prostanoids contribute to fever The roles of PGs in various physiological and patho- generation, but the identity of the prostanoids involved physiological processes have thus far been suggested by has remained elusive. Ushikubi et al. (7) clarified this comparing the effects of aspirin-like drugs with those issue by showing that EP3-deficient mice fail to respond of each prostanoid added exogenously. However, such to either exogenous or endogenous pyrogens. A similar studies do not clearly indicate which type of prostanoid approach might be adopted to elucidate the mechanism and which class of prostanoid receptor is involved in a of other features of systemic illness. For instance, given given process, nor how critical the actions of the role of PGD2 in sleep cycles,