EP2 and EP4 prostanoid receptor signaling
Introduction
Prostaglandin E2 (PGE2) is one of five major products produced by the initial actions of the cyclooxygenases on arachidonic acid. The other four products are PGF2α, PGD2, PGI2 and thromboxane A2 (TxA2). Collectively these products are referred to as prostanoids and the receptors that mediate their actions are known as prostanoid receptors. There are two cyclooxygenases, abbreviated COX-1 and COX-2, that convert arachidonic acid to PGH2 (Smith et al., 2000). COX-1 is constitutively expressed in most tissues, although the level of its expression can be affected by a number of factors. COX-2 expression is more tightly regulated and under most normal physiological conditions it is not expressed. However, under a variety of pathophysiological conditions its expression can be rapidly induced. PGH2 is the initial metabolite produced by both enzymes, which is then converted to the final products through the actions of specific synthases. For example, PGE2 synthase (PGES) catalyzes the conversion of PGH2 to PGE2. There are three forms of this enzyme that are uniquely different from one another (Kamei et al., 2003). One is found in the cytosol and is referred to as cPGES. The other two are found in microsomal fractions and are abbreviated mPGES1 and mPGES2. The expression of mPGES1 is inducible and appears to be correlated with the expression of COX-2 (Murakami et al., 2000).
The prostanoid receptors are in the superfamily of G-protein coupled receptors (GPCR). These receptors were first defined pharmacologically as EP, FP, DP, IP and TP, which referred to the endogenous ligands that activated these receptors, i.e. PGE2, PGF2α, PGD2, PGI2 and TxA2 (Coleman et al., 1994b). There is considerable heterogeneity of the prostanoid receptors due to the presence of genes encoding separate subtypes and due to alternative mRNA splicing. For the EP receptors there are four subtypes that are the products of separate genes (EP1, EP2, EP3 and EP4). Additionally there are two alternative splice variants of the EP1 receptor and eight variants of the EP3 receptor.
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Cloning of the EP receptors
Initially there was some confusion regarding the identity of the cloned EP2 and EP4 receptors because it was previously thought that there were only three EP receptors and only one, the EP2, was thought to be coupled to the stimulation of adenylyl cyclase. The remaining EP1 and EP3 receptors were defined as coupling, respectively, to either the activation of phospholipase C or the inhibition of adenylyl cyclase. The first two EP receptors to be cloned were the EP3 (Sugimoto et al., 1992) and
Structure and regulation of the EP2 and EP4 receptors
Fig. 1 shows an alignment of the primary amino acid sequences of the human EP2 and EP4 receptors and their amino acid identity. Although sharing obvious similarities in their pharmacology and functional coupling, they only share approximately 38% identity in their transmembrane domains, which is not appreciably different from the amino acid identity they share with the EP1 (37%) and EP3 (34%) receptors. In fact, phylogenetic analysis shows that the EP2 receptor is actually more closely related
Second messenger signaling of the EP2 and EP4 receptors
As stated previously, with respect to second messenger signaling, the distinguishing feature of the EP2 and EP4 prostanoid receptors was their ability to stimulate intracellular cAMP formation. This was demonstrated following the cloning of both of these receptors and their transient expression in COS cells. For the EP4 receptor stimulation with PGE2 produced an ~8 fold increase in cAMP formation over untransfected COS cells (Honda et al., 1993); while for the EP2 receptor, PGE2 stimulated cAMP
Knockout studies of the EP2 and EP4 receptors
The use of gene knockout studies to create animals lacking the various prostanoid receptors has contributed significantly to our understanding of their potential physiology and pathophysiology (Kobayashi and Narumiya, 2002). This is especially true of the EP2 and EP4 receptors since prior the cloning of these receptors it was thought that all the effects of PGE2 involving the activation of adenylyl cyclase were through one receptor subtype. Table 1, Table 2 list studies in which the use of
Acknowledgements
I would like to thank Dr. Hiromichi Fujino for his contributions to this work and Sambhitab Salvi for his help with Fig. 1. The following organizations for their support: the National Eye Institute (EY11291), Allergan Inc., and the Arizona Disease Control Research Commission.
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