Biology:Prostaglandin D2 receptor
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:
- Prostaglandin D2 receptor 1 (DP1) - PTGDR1
- Prostaglandin D2 receptor 2 (DP2) - PTGDR2
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
References
- ↑ 1.0 1.1 1.2 "The prostaglandin D2 receptor 2 pathway in asthma: a key player in airway inflammation". Respiratory Research 19 (1): 189. September 2018. doi:10.1186/s12931-018-0893-x. PMID 30268119.
- ↑ 2.0 2.1 2.2 "The pharmacology of the prostaglandin D2 receptor 2 (DP2) receptor antagonist, fevipiprant". Pulmonary Pharmacology & Therapeutics 68: 102030. June 2021. doi:10.1016/j.pupt.2021.102030. PMID 33826946.
- ↑ "PTGDR prostaglandin D2 receptor [Homo sapiens (human) - Gene - NCBI"]. https://www.ncbi.nlm.nih.gov/gene/5729#bibliography.
- ↑ 4.0 4.1 4.2 "Molecular cloning and characterization of the human prostanoid DP receptor". The Journal of Biological Chemistry 270 (32): 18910–18916. August 1995. doi:10.1074/jbc.270.32.18910. PMID 7642548.
- ↑ 5.0 5.1 5.2 "The prostaglandin D2 receptor (PTGDR) gene in asthma and allergic diseases". Allergologia et Immunopathologia 42 (1): 64–68. January 2014. doi:10.1016/j.aller.2012.12.002. PMID 23410912.
- ↑ 6.0 6.1 "Multiple roles of the prostaglandin D2 signaling pathway in reproduction" (in en-US). Reproduction 149 (1): R49–R58. January 2015. doi:10.1530/REP-14-0381. PMID 25269616.
- ↑ "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. September 2018. doi:10.1186/s12974-018-1305-3. PMID 30236122.
External links
- Prostaglandin+D2+Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
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