User:Nmneuro/Prostaglandin D2 receptor

OUTLINE: LEAD, RECEPTOR STRUCTURE, SIGNAL TRANSDUCTION PATHWAY, PHYSIOLOGICAL FUNCTIONS

Lead: The prostaglandin D2 (PGD2) receptors, also known as DP receptors, are important for various functions of the central nervous system and 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.

Receptor Structure
The biosynthesis of the prostaglandin D2 receptor begins with the oxidation of arachidonic acid by enzymes named cyclooxegenase-1 and cyclooxegenase-2 to prostaglandin G2 (PGG2). The same enzymes then catalyze the reduction of PGG2 to prostaglandin H2 (PGH2). PGH2 is an unstable endoperoxide that serves as the substrate for five different prostaglandin synthase enzymes, for which the specific synthase used determines the receptor produced. PTGDR is synthesized when synthase enzyme PGDS reacts with PGH2, and further enzymatic reactions result in the two receptor subtypes, PTGDR1 and PTGDR2.

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

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. Protein kinase C can also phosphorylate the prostaglandin D2 receptor at two sites in the first and second cytoplasmic loops as well as six sites in the COOH terminus.

Signal Transduction Pathway
In 2014, García-Solaesa et. al. described that the signaling pathway by which the PGD2 receptor mediates its effects begins with the binding of prostaglandin D 2. 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 adenosine monophosphate, 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.

However, several other researchers make distinctions between the two prostaglandin D 2 receptor subtypes and their G protein-coupled receptor pathways. 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. These distinctions in signal transduction pathways mediate the different effects of these PDG2 receptor subtypes.

Physiological Functions

 * 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. 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.
 * 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.
 * Neurodegeneration: A 2018 study induced the prostaglandin D2 signaling pathway in mice via PTGDR2 to determine the impact on Parkinson's Disease-like pathology. 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.