Prostanoid receptors have been classified into TX receptor (TP), PGE receptor (EP1, EP2, EP3, and EP4), PGF receptor (FP), PGI receptor (IP), and PGD receptor (DP; references 8
). In view of the structure, CRTH2 appears to be unique among members of prostanoid receptors in that it lacks any consensus amino acid sequence motifs that are shared by all other known prostanoid receptors 10
. Indeed, a phylogenetic analysis shows that CRTH2 is more akin in the overall structure to the FPR subfamily members and receptors for LTs than known prostanoid receptors (). Furthermore, the chromosomal location of CRTH2 (11q12.2) (sequence data available from GenBank/EMBL/DDBJ under accession no. AC004126) differs from those of other receptors listed in , suggesting that CRTH2 might form a novel receptor gene subfamily. The mechanisms by which CRTH2 binds PGD2
with an affinity as high as DP remain to be clarified.
Figure 4 A phylogenetic tree for human receptors to classical chemoattractants and major prostanoids. The tree was constructed by the N-J method using CLUSTAL X software. The sequence of the human α2B adrenergic receptor was used as an outer group to obtain (more ...)
is currently considered to elicit its biological actions through DP 810
. In fact, well-established PGD2
-induced activities such as vasodilation, relaxation of other various smooth muscles, and inhibition of platelet aggregation are apparently mediated by DP because they are also induced by a DP-specific agonist BW245C 1819
. However, several in vivo and ex vivo effects of PGD2
such as an increase in microvascular permeability, eosinophil infiltration, and goblet cell depletion are not mimicked by BW245C 20
. Thus, questions on the existence of a BW245C-insensitive PGD2
receptor subtype(s) has been repeatedly proposed 202122
. In addition, although DK-PGD2
is generally thought to be biologically inactive in many systems, several investigators actually observed its effects on some PGD2
-sensitive tissues 23
. Our finding that CRTH2 is the novel PGD2
receptor functioning differently from DP may lead to the resolution of such long-standing questions.
A notable difference between CRTH2 and DP is the signaling molecules: Gαi is used for CRTH2 whereas Gαs is for DP. As shown by many cell types with Gαi-coupled receptors, CRTH2 leads Th2 cell, eosinophil, and basophil induction of chemotaxis/chemokinesis in response to PGD2
. Consequently, these types of cells may accumulate at the sites of allergic inflammation 34
. Indeed, it was demonstrated that topical application of PGD2
causes significant accumulation of eosinophils in the guinea pig conjunctiva and the dog trachea 2024
. In contrast, DP-mediated PGD2
signals caused reduction in spontaneous cell migration in DP-transfected Jurkat cells and had no effect on the migration of DP-expressing basophils in our study. These results suggest that DP-mediated signals may not, in nature, lead to chemotactic or chemokinetic behavior in leukocytes. Although PGD2
has been reported to modulate various activities of neutrophils, we could not detect any substantial expression of CRTH2 or DP in blood neutrophils 25
. However, further studies are required to finally establish the actual involvement of these receptors in the PGD2
-induced modulation of neutrophils.
Although the mechanisms by which DP contributes to the formation of allergic inflammation remain to be clarified, our results suggest that DP and CRTH2 may be cooperatively involved in allergic inflammation through different processes. A plausible scenario could be that PGD2
is largely produced by mast cells upon antigen stimulation, inducing local vasodilation via DP, which enhances extravasation of blood leukocytes 26
, followed by chemotactic migration of Th2 cells, eosinophils, and basophils via CRTH2 in cooperation with other chemotactic mediators such as CC chemokines TARC and eotaxin 2728
. Thus, CRTH2 may be a new favorable target for allergic disease therapies. Generation of selective inhibitors for CRTH2 or CRTH2-deficient mice should help to elucidate the physiological and pathophysiological roles of the CRTH2/PGD2
system and its relative importance in the host defense mechanisms.