Prostaglandin DP1 receptor

The prostaglandin D₂ receptor 1 (DP₁), a G protein-coupled receptor encoded by the PTGDR gene (also termed PTGDR1), is primarily a receptor for prostaglandin D₂ (PGD₂). The receptor is a member of the prostaglandin receptors belonging to the subfamily A14 of rhodopsin-like receptors. Activation of DP₁ by PGD₂ or other cognate receptor ligands is associated with a variety of physiological and pathological responses in animal models.

Gene

The PTGDR gene is located on chromosome 14 at position q22.1, (i.e. 14q22.1), a chromosomal locus associated with asthma and other allergic disorders. PTGDR, which consists of 4 introns and 5 exons, encodes for a ~44 kilodalton protein but also multiple alternative spliced transcript variants.

Expression

DP₁ is expressed primarily by cells involved in mediating allergic and inflammatory reactions, i.e. human and rodent mast cells, basophils, and eosinophils, Th2 cells, and dendritic cells, and by cells contributing to these reactions, i.e. human and/or rodent airway epithelial cells, vascular endothelium, mucus-secreting goblet cells in the nasal and colonic mucosa, and serous gland cells of the nose. DP₁ protein is expressed in mouse placenta and testes and mRNA transcripts have also been detected in the meninges of the mouse brain by multiple reports and, by single reports, in the rat meninges as well as the mouse thalamus, hippocampus, cerebellum, brainstem, and retina.

Ligands

Activating ligands

PGD₂ binds to and activates DP₁ at concentrations in the 0.5 to 1 nanomolar range. Relative potencies in binding to and activating DP₁ for the following prostanoids are: PGD₂>>PGE₂>prostaglandin F_2α>PGI₂=thromboxane A2, with PGD₂ being more than 100-fold more potent than PGE₂ in binding to and stimulating DP₁. PDJ2, Δ12-PDJ2, and 15-deoxy-Δ12,14-PGJ2, which form in vitro and in vivo rapidly as non-enzymatic rearrangements of PGD₂ (see cyclopentenone prostaglandins), also bind to and activate DP₁, with PDJ2 doing so almost as effectively as PDG2 and the latter two PGJs doing so 100-fold and 300-fold less potently than PDG2. Other compounds, e.g. L-644,698, BW 245C, BW A868C, and ZK 110841, have been synthesized, found to be about as potent as PGD₂ in binding to and stimulating DP₁, and used to study the function of this receptor.

The drug treprostinil is a high affinity ligand for and potent activator of not only DP₁ but also two other prostanoid receptors, EP₂ and IP.

Inhibiting ligands

Asapiprant (S-555739) and laropiprant are selective receptor antagonists of DP₁ whereas vidupiprant is a receptor antagonist for both DP₁ and DP₂.

Mechanisms of cell activation

Among the 8 human prostanoid receptors, DP₁, along with IP, EP₂, and EP₄, are classified as relaxant prostanoid receptors; each, including DP₁, is a G protein-coupled receptors that works by activating G-S proteins which in turn raises cellular cAMP levels thereby mobilizing cyclic adenosine monophosphate-activated cell signaling pathways which regulate cell function. DP₁ activation also causes the mobilization of calcium in HEK293 cells transfected with this receptor. It does so by a mechanism that is independent of inositol trisphosphate signaling; Ligand-activated DP₁ also mobilizes G protein-coupled receptor kinase 2 (GRK2, also known as β-adrenergic receptor kinase 2 [BARK1]) and arrestin 2 (also known as arrestin beta 1 [ARRB1]). These agents act to uncouple DP₁ from its G proteins and to internalize in a process that limits the DP₁'s cell-activation life-time in a process termed homologous desensitization. Activation of protein kinase Cs likewise trigger DP₁ to uncouple from G proteins and internalize although in model studies DP₁ has not been shown to cause the activation of PKC (see Protein kinase C#Function).

Activities

Allergy

Tissue studies

Studies in mouse as well as human tissues and cells find that DP₁ stimulation has numerous pro-allergic effects. DP₁ activation blocks the production of interleukin 12 by dendritic cells; this biases the development of naïve T lymphocytes to Th-2 rather than Th-1 helper cells and thereby promotes allergic rather than non-allergic inflammatory responses (see T helper cell#Th1/Th2 Model for helper T cells and T helper cell#Limitations to the Th1/Th2 model. DH1 activation also promotes allergic reactions by suppressing the function of natural killer cells, prolonging the survival of eosinophils, and stimulation the maturation of dermal mast cell.

Animal studies

Studies of experimentally-induced allergic responses in animals further implicate DP₁ in allergy. DP₁ gene knockout and/or DP₁ inhibition by receptor antagonists markedly reduces airway inflammation, obstruction, hypersensitivity, and pro-allergic cytokine and chemokine production in a mouse model of ovalbumin-induced asthma as well as allergic symptoms in a guinea pig model of allergic conjunctivitis, rhinitis, and asthma. The administration of PGD₂ into the skin of rats or into the eyes of rabbits causes local symptoms of allery. These responses are thought, but not yet proved, to be mediated by DP₁ activation. In contrast to these results, however, activation of DP₁ by intratrachael administration of a selective DP₁ activator activated DP₁ on dendritic cells to suppress airway allergic inflammation by increasing the number of Foxp3+ CD4+ regulatory T cells. Furthermore, DP₁ activation reduces eosinophilia in allergic inflammation and blocks antigen-presenting langerhans cell function in mice. This results suggest that DP₁ can promote or suppress allergic responses depending on the animal model tested and, perhaps, the type of allergic reaction investigated.

Human studies

Allergen inhalation challenge of humans produces rises in the PGD₂ levels in their bronchoalveolar lavage fluids. Furthermore, the administration of PGD₂ into the nose or skin of human volunteers produces local symptoms of allergy and the inhalation of PGD₂ into asthmatics causes constriction of the airways as well as the potentiation of airway constriction responses. These reactions, similar to those produced in animal studies, may be mediated by DP₁.

Central nervous system

PGD₂ is the most abundant prostanoid in the brains of humans and other mammals and DP₁ receptors are located on arachnoid mater trabecular cells in mouse basal forebrain. The PGD₂-DP₁ pathway is involved in the regulation of non-rapid eye movement sleep in rodents: infusion of PGD₂ into the lateral ventricle of mice or the brain of rats induces an increase in the amount of non-rapid eye movement sleep in wild-type (WT) but not DP₁-deficient animals. This sleep-induction appears to involve the DP₁-dependent stimulation of adenosine formation and subsequent simulation of the adenosine A2A receptor by adenosine. In humans, a genetic variant of ADA associated with the reduced metabolism of adenosine to inosine has been reported to deep sleep and SWA during sleep. These studies suggest that DP₁ has a similar role in the sleep of humans.

Pulmonary hypertension

Pulmonary arterial hypertension in humans is commonly treated with specific pulmonary artery vasodilators that increase survival such as the prostacyclin I₂ (PGI₂) mimetics including treprostinil, epoprostenol, iloprost, and beraprost. Recent studies find that DP₁ as well as the PGI₂ receptor protein are expressed in human pulmonary arteries and veins; that treprostinil but not iloprost caused pulmonary vein relaxation in part by acting through DP₁ in insolated human pulmonary vascular preparations; and that the effect of treprostinil on DP₁ in human pulmonary veins may contribute to its therapeutic efficacy in primary pulmonary hypertension.

Reproduction

Studies in male mice indicate that DP₁ activation induces the translocation of SOX9 into the nucleus thereby signaling for the maturation of Sertoli cells and embryonic gonads. Disruption of this DP₁-activated circuit leads to disordered maturation of the male reproductive organs such as cryptorchidism (i.e. failure of testes descent into the scrotum) in mice and, it is suggested, may also do so in humans.

Genomics studies

Human genomics studies have associated single-nucleotide polymorphism variants with an increased incidence of allergic diseases. Studies in two different populations have replicated associations between -549T>C, -441C>T, and -197T>C variants and a study in a single population has associated the -613C>T variation with increased incidences of nasal polyposis, asthma, and/or aspirin sensitivity; the -197T>C and -613 C>T variants were also associated with increased incidences of allergic reactions to pollen and mites. A single population study associated the -731A>C variant and studies in two different population associated the 6651C>T variant with increased incidences of asthma and/or bronchial hyper-reactivity. The intrinsic variants rs17831675, rs17831682, and rs58004654 (now termed rs7709505) have been associated with an increased incidence of asthma in single population studies. A metaanalasis −549 C/T, −441 C/T, and −197 C/T found that of these three variants, only −549 C/T conferred susceptibility to asthma in Europeans and that this susceptibility was limited to adults.

See also

• Prostaglandin receptors
• Prostanoid receptors
• Prostaglandin DP₂ receptor
• Eicosanoid receptor

References

Further reading

External links