The Prostanoid Receptors

The idea that extracellular prostanoids exert their biological actions by activating selective membrane receptors is based on three lines of pharmacological evidence (for review, see refs. 54 and 55). Functional studies show that low concentrations of prostanoids elicit distinct sets of responses in different tissues. In some cases, such responses can be selectively mimicked by synthetic prostanoid agonists, or prevented by prostanoid antagonists. Studies with radio-actively labeled ligands lend support to these observations spe- 

Receptor subtype Selective agonist Selective antagonist Tissue Distribution Biological effects T ransduction system 

DP BW245C BWA868C platelets, smooth muscle, CNS smooth muscle relaxation, inhib. platelet aggregation, sleep cAMP 

EPi lloprost (also an IP agonist) AH6809 smooth muscle smooth muscle contraction [Calcium]-, 

EP2 Butaprost None smooth muscle, leukocytes,mast cells, sensory neurons, lung, kidney smooth muscle relaxation, Inhib. mast cell secretion, stim. Intestinal secretion cAMP 

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The prostanoid receptors are G-protein coupled rhodopsin-type receptors with seven transmembrane domains [6] (Fig. 3). The overall homology among the receptors is not high, though these receptors conserve the important amino acid sequences in several regions, especially in the seventh transmembrane domain. 

Since molecular cloning of the prostanoid receptors, the research in this field has been evolved quite fast. Information obtained from the studies on the receptor... 

Kobayashi, T., Kiriyama, M, Hirata, T Hirata, M., Ifshikubi, F., and Nammiya, S. (1997). Identification of domains conferring ligand binding specificity to the prostanoid receptor J. Bioi Cfiem. 272, 15154-15160,... 

The properties of the prostanoid receptors, such as second messengers in signal transduction pathways, and localization in the eye are summarized in Table 2.1. Prostanoid receptors are widely distributed in the monkey and human eyes [5]. The expression and localization of the FP and EP receptor subtypes in the tissues was studied intensely by in-situ hybridization and immunohistochemistry to gain a better understanding of the ocular effects of the prostanoids and their analogues. This work suggests a wide distribution but differential expression of FP and EP receptor subtypes in human ocular tissues. The highest expression of FP receptor mRNA and protein was found in the corneal epithelium, ciliary... 

Specific to the prostanoid receptors, the most conserved region is the seventh transmembrane domain, where the sequence L-X-A-X-R-X-A-SIT-X-N-Q-I-L-D-P-W-V-Y-I-L is shared. Two further sequences, G-R-Y-X-X-Q-X-P-G-T/S-W-C-F and M-X-F-F-G-L-X-X-L-L-X-X-X-A-M-A-X-E-R, are also present in the second extracellular loop and third transmem-... 

Figure 6.3. Molecular grouping of the prostanoid receptors. The dendogram was constructed from sequence comparison of the published sequences of the cloned prostanoid receptors from various species. The sequences used are identified ty their accession numbers shown within the figure. The length of the solid lines represent evolutionary diversity.

Coleman, R.A. and Kennedy, I. (1985). Characterization of the prostanoid receptors mediating contraction of guinea pig isolated trachea. Prostaglandins, 29, 363-375... 

Prostacyclin receptors (IP) mediate the effects of prostacyclin, although this is the least selective of the prostanoid receptors. Agonists, in order of relative binding affinity strength, include PGE PGF, = PGD. The effects of prostacyclin are numerous (e.g. vasodilator, hyperalgesic, inhibits platelet aggregation). The IP receptor is most closely related in sequence to the DP receptor, and most evidence indicates that IP signals via a stimulation of cAMP (Breyer et al, 2001 Ullrich et al, 2001). 

Fig. 5.8. Phylogenetic comparison of the prostanoid receptor family. Sequence analysis allowed definition of two main subfamilies of prostanoid receptors, which may also be distinguished by their different signal transduction mechanisms. (Redrawn from ref. 69.)...

Uski, T. K., Andersson, K. E., Brandt, L., Ljunggren, B., 1984 Characterization of the prostanoid receptors and of the contractile effects of prostaglandin F2a in human pial arteries. Acta Physiol. Scand. In Press. 

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