Prostaglandin D2 receptor

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The prostaglandin D2 (PGD2) receptors are G protein-coupled receptors that bind and are activated by prostaglandin D2. [1] [2] Also known as PTGDR or DP receptors, they are important for various functions of the nervous system and inflammation. They include the following proteins:

Contents

Structure

The PTGDR gene that encodes the prostaglandin D2 receptor in humans is found on the long arm of chromosome 14 at 14q22.1 and consists of four exons. [3] A 1995 molecular cloning study of the prostaglandin D2 receptor derived from humans found that the corresponding cDNA encoded for a protein with 359 amino acids and molecular mass of 40,276 daltons. [4] The receptor is a heterotrimeric G protein-coupled receptor, containing seven rhodopsin-like transmembrane domains, an extracellular NH2 terminus, and an intracellular COOH terminus. [2]

The receptor contains a few structural sites at which it can interact with other molecules. For instance, there are three possible sites for N-glycosylation at the Asn-10, Asn-90, and Asn-297 residues. [4] Protein kinase C can also phosphorylate the prostaglandin D2 receptor at two sites in the first and second cytoplasmic loops as well as at six sites in the COOH terminus. [4]

Signal transduction pathway

A 2014 journal article described that the PGD2 receptor signaling pathway begins with the binding of prostaglandin D2. [5] After PDG2 binds to the extracellular ligand site on the receptor, the Gs alpha subunit is activated. Activation of the Gs alpha subunit prompts activation of the enzyme adenylate cyclase, which is located on the cell membrane. Adenylate cyclase then catalyzes the change from ATP to cyclic AMP, or cAMP. The result of the PDG2 receptor signaling pathway is a rise in levels of second messenger cAMP, which can proceed to perform other tasks depending on the activated cell. [5]

However, several other researchers make distinctions between the two prostaglandin D2 receptor subtypes and their G protein-coupled receptor pathways. [2] [6] They describe that the binding of PDG2 to PTGDR1 activates the Gs alpha subunit, resulting in the subsequent increase of cAMP. This stimulation of cAMP also involves activation of Protein Kinase A and influx of calcium ions through membrane channels. In contrast, the binding of PDG2 to PTGDR2 instead activates the Gi alpha subunit, decreasing cAMP levels and increasing intracellular calcium ion levels through inositol phosphate. [6] These distinctions in signal transduction pathways mediate the different effects of these PDG2 receptor subtypes.

Disease relevance

Inflammation: PTGDR1 signaling results in many non-inflammatory effects, such as inhibition of dendritic cell and Langerhans cell migration and eosinophil apoptosis. PTGDR2 mediates several pro-inflammatory effects, including the stimulation of TH2 cells, ILC2, and eosinophils. [1]

Asthma: Activation of PTGDR2 amplifies an inflammation cascade by upregulating the expression and release of type 2 cytokines through TH2 cells, ILC2 cells, and eosinophils. [1] These type 2 cytokines lead to symptoms like airway inflammation, increased mucus production, and mucus metaplasia, which are found in asthma conditions. Increase in PTGDR1 signal transduction results in vasodilation, which can promote the migration and likelihood of survival for inflammatory cell types. [5]

Neurodegeneration: A 2018 study induced the prostaglandin D2 signaling pathway in mice via PTGDR2 to determine the impact on Parkinson's Disease-like pathology. [7] The researchers observed that the mice with PG treatment developed loss of dopamine neurons in the substantia nigra pars compacta, motor deficits, and other progressive disease-like symptoms. They also discovered PGD2 receptors on dopaminergic cells but not on microglia.

See also

Related Research Articles

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<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interleukin 13</span> Protein and coding gene in humans

Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. IL-13 was first cloned in 1993 and is located on chromosome 5q31.1 with a length of 1.4kb. It has a mass of 13 kDa and folds into 4 alpha helical bundles. The secondary structural features of IL-13 are similar to that of Interleukin 4 (IL-4); however it only has 25% sequence identity to IL-4 and is capable of IL-4 independent signaling. IL-13 is a cytokine secreted by T helper type 2 (Th2) cells, CD4 cells, natural killer T cell, mast cells, basophils, eosinophils and nuocytes. Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation. It is a mediator of allergic inflammation and different diseases including asthma.

<span class="mw-page-title-main">Thromboxane receptor</span> Mammalian protein found in Homo sapiens

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Prostaglandin D<sub>2</sub> Chemical compound

Prostaglandin D2 (or PGD2) is a prostaglandin that binds to the receptor PTGDR (DP1), as well as CRTH2 (DP2). It is a major prostaglandin produced by mast cells – recruits Th2 cells, eosinophils, and basophils. In mammalian organs, large amounts of PGD2 are found only in the brain and in mast cells. It is critical to development of allergic diseases such as asthma. Research carried out in 1989 found PGD2 is the primary mediator of vasodilation (the "niacin flush") after ingestion of niacin (nicotinic acid).

Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2,, PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2. They are named based on the prostanoid to which they preferentially bind and respond, e.g. the receptor responsive to PGI2 at lower concentrations than any other prostanoid is named the Prostacyclin receptor (IP). One exception to this rule is the receptor for thromboxane A2 (TP) which binds and responds to PGH2 and TXA2 equally well.

Prostaglandin DP<sub>1</sub> receptor Protein-coding gene in the species Homo sapiens

The Prostaglandin D2 receptor 1 (DP1), a G protein-coupled receptor encoded by the PTGDR1 gene (also termed PTGDR), 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.

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Gi protein alpha subunit is a family of heterotrimeric G protein alpha subunits. This family is also commonly called the Gi/o family or Gi/o/z/t family to include closely related family members. G alpha subunits may be referred to as Gi alpha, Gαi, or Giα.

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Prostaglandin DP<sub>2</sub> receptor Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Prostacyclin receptor</span> Mammalian protein found in Homo sapiens

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<span class="mw-page-title-main">Setipiprant</span> Chemical compound

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<span class="mw-page-title-main">5-Oxo-eicosatetraenoic acid</span> Chemical compound

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References

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  2. 1 2 3 Brightling C, Kulkarni S, Lambrecht BN, Sandham D, Weiss M, Altman P (June 2021). "The pharmacology of the prostaglandin D2 receptor 2 (DP2) receptor antagonist, fevipiprant". Pulmonary Pharmacology & Therapeutics. 68: 102030. doi:10.1016/j.pupt.2021.102030. PMID   33826946. S2CID   233184866.
  3. ↑ "PTGDR prostaglandin D2 receptor [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-05-13.
  4. 1 2 3 Boie Y, Sawyer N, Slipetz DM, Metters KM, Abramovitz M (August 1995). "Molecular cloning and characterization of the human prostanoid DP receptor". The Journal of Biological Chemistry. 270 (32): 18910–18916. doi: 10.1074/jbc.270.32.18910 . PMID   7642548.
  5. 1 2 3 García-Solaesa V, Sanz-Lozano C, Padrón-Morales J, Hernández-Hernández L, García-Sánchez A, Rivera-Reigada ML, et al. (January 2014). "The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases". Allergologia et Immunopathologia. 42 (1): 64–68. doi:10.1016/j.aller.2012.12.002. PMID   23410912.
  6. 1 2 Rossitto M, Ujjan S, Poulat F, Boizet-Bonhoure B (January 2015). "Multiple roles of the prostaglandin D2 signaling pathway in reproduction". Reproduction. 149 (1): R49–R58. doi: 10.1530/REP-14-0381 . PMID   25269616.
  7. ↑ Corwin C, Nikolopoulou A, Pan AL, Nunez-Santos M, Vallabhajosula S, Serrano P, et al. (September 2018). "Prostaglandin D2/J2 signaling pathway in a rat model of neuroinflammation displaying progressive parkinsonian-like pathology: potential novel therapeutic targets". Journal of Neuroinflammation. 15 (1): 272. doi: 10.1186/s12974-018-1305-3 . PMC   6146649 . PMID   30236122.
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