Prostanoids exert significant effects on circulatory beds. They play a role in the response of the vasculature to adjustments in perfusion pressure and oxygen and carbon dioxide tension, and they mediate the actions of numerous factors. The role of prostanoids in governing circulation of the perinate is suggested to surpass that in the adult. Prostanoids are abundantly generated in the perinate. They have been implicated in autoregulation of blood flow as studied in brain and eyes. Prostaglandins are also dominant regulators of ductus arteriosus tone. The effects of these autacoids are mediated through specific G protein-coupled receptors. In addition to the pharmacological characterization of the prostanoid receptors, important advances in understanding the biology of these receptors have been made in the last decade. Their cloning and the development of animals with disrupted genes of these receptors have been very informative. The involvement of prostanoid receptors in the developing subject, especially on brain and ocular vasculature and on ductus arteriosus, has also begun to be investigated; the expression of these receptors changes with development. Some but not all of the ontogenic changes in these receptors are attributed to homologous regulation. Interestingly, in the process of elucidating their effects, functional perinuclear prostaglandin E 2 receptors have been uncovered. This article reviews prostanoid receptors and addresses implications on the developing subject with attention to vascular physiology.

This study demonstrates the localization of the prostaglandin (PG)D 2 receptor (DP) within the mucous‐secreting globlet cells of the human colon by in situ hybridization, which suggests a role for DP in mucous secretion. Selective high affinity ligands were used, therefore, to evaluate DP regulation of mucous secretion in LS174T human colonic adenocarcinoma cells. The expression of hDP in LS174T cells was confirmed at the mRNA level by reverse transcriptase‐polymerase chain reaction, and at the protein level by radioligand binding assays and signal transduction (cyclic AMP accumulation) assays. PGD 2 and the highly selective DP‐specific agonist L‐644,698 ((4‐(3‐(3‐(3‐hydroxyoctyl)‐4‐oxo‐2‐thiazolidinyl) propyl) benzoic acid) (racemate)), but not PGE 2 competed for [ 3 H]‐PGD 2 ‐specific binding to LS174T cell membranes ( K i values of 0.4 n M and 7 n M , respectively). The DP‐specific agonists PGD 2 , PGJ 2 , BW245C (5‐(6‐carboxyhexyl)‐1‐(3‐cyclohexyl‐3‐hydroxypropylhydantoin)), and L‐644,698 showed similar potencies in stimulating cyclic AMP accumulation (EC 50 values: 45–90 n M ) and demonstrated the expected rank order of potency. PGE 2 also elicited cyclic AMP production in this cell line (EC 50 value: 162 n M ). The activation of cyclic AMP production by PGD 2 and L‐644,698, but not PGE 2 , was inhibited by the selective DP antagonist BW A868C. Thus, PGD 2 and L‐644,698 act through hDP in LS174T cells. PGD 2 , L‐644,698 and PGE 2 (an established mucin secretagogue) potently stimulated mucin secretion in LS174T cells in a concentration‐dependent manner (EC 50 <50 n M ). However, BW A868C effectively antagonized only the mucin secretion mediated by PGD 2 and L‐644,698 and not PGE 2 . These data support a role for the DP receptor in the regulation of mucous secretion. British Journal of Pharmacology (2000) 131 , 1537–1545; doi: 10.1038/sj.bjp.0703688

We report the cloning, functional expression and cell-specific localization of the rat homologue of the prostaglandin D2 receptor (DP). In situ hybridization, utilizing multiple digoxigenin-labelled riboprobes and their complementary sense controls, was performed to determine the detailed distribution of DP receptor mRNA in the central nervous system and the gastrointestinal tract. Within the brain, the leptomeninges and choroid plexus expressed DP receptor mRNA. Transcripts detected in the spinal cord were localized to the sensory and motor neurons of the dorsal and ventral horns, respectively, suggesting a role for the DP receptor in the modulation of central nervous system processes, including pain transmission. Within the gastrointestinal tract (stomach, duodenum, ileum and colon) signals were highly localized to the mucous-secreting goblet cells and the columnar epithelium. These findings suggest a novel biological role for prostaglandin D2-mediated activity at the DP receptor, namely mucous secretion. In addition, radioligand binding assays (saturation analyses and equilibrium competition assays) and functional assays (measuring cAMP accumulation) were performed to characterize the recombinant rat DP receptor expressed in human embryonic kidney (HEK) 293(EBNA) cells. A single site of binding (K(D) = 14 nM, Bmax = 115 fmol/mg protein) was measured for prostaglandin D2-specific binding to the rat DP receptor. Prostaglandin D2 proved to be a potent agonist at the rat DP receptor (EC50 = 5 nM). The rank order of efficacy for DP receptor specific agonists [prostaglandin D2 = prostaglandin J2 = BW 245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropylhydantoin)) > L-644,698 ((4-(3-(3-(3-hydroxyoctyl)-4-oxo-2-thiazolidinyl) propyl) benzoic acid) (racemate)] reflected the affinity with which the ligands bound to the receptor.

A human embryonic kidney cell line [HEK 293(EBNA)] stably expressing the human recombinant prostaglandin D 2 (PGD 2 ) receptor (hDP) has been characterized with respect to radioligand binding and signal transduction properties by use of prostanoids and prostanoid analogues. Radioligand binding studies included saturation analyses, the effects of nucleotide analogues, the initial rate of ligand‐receptor association and equilibrium competition assays. In addition, adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) generation in response to ligand challenge was also measured, as this is the predominant hDP signalling pathway. L‐644,698 ((4‐(3‐(3‐(3‐hydroxyoctyl)‐4‐oxo‐2‐thiazolidinyl) propyl) benzoic acid) (racemate)) was identified as a novel ligand having high affinity for hDP with an inhibitor constant ( K i ) of 0.9 n m . This K i value was comparable to the K i values obtained in this study for ligands that have previously shown high affinity for DP: PGD 2 (0.6 n m ), ZK 110841 (0.3 n m ), BW245C (0.4 n m ), and BW A868C (2.3 n m ). L‐644,698 was found to be a full agonist with an EC 50 value of 0.5 n m in generating cyclic AMP following activation of hDP. L‐644,698 is, therefore, comparable to those agonists with known efficacy at the DP receptor (EC 50 ): PGD 2 (0.5 n m ), ZK 110841 (0.2 n m ) and BW245C (0.3 n m ). L‐644,698 displayed a high degree of selectivity for hDP when compared to the family of cloned human prostanoid receptors: EP 1 (>25,400 fold), EP 2 (∼300 fold), EP 3‐III (∼4100 fold), EP 4 (∼10000 fold), FP (>25,400 fold), IP (>25,400 fold) and TP (>25,400 fold). L‐644,698 is, therefore, one of the most selective DP agonists as yet described. PGJ 2 and Δ 12 ‐PGJ 2 , two endogenous metabolites of PGD 2 , were also tested in this system and shown to be effective agonists with K i and EC 50 values in the nanomolar range for both compounds. In particular, PGJ 2 was equipotent to known DP specific agonists with a K i value of 0.9 n m and an EC 50 value of 1.2 n m . British Journal of Pharmacology (1998) 123 , 1317–1324; doi: 10.1038/sj.bjp.0701708