The prostaglandin D
2 (PGD
2) receptors are
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
s that bind and are activated by
prostaglandin D2.
Also known as PTGDR or DP receptors, they are important for various functions of the nervous system and inflammation. They include the following
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s:
*
Prostaglandin D2 receptor 1 (DP
1) -
*
Prostaglandin D2 receptor 2 (DP
2) -
Structure
The PTGDR gene that encodes the 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 prostaglandin D2 receptor derived from humans found that the corresponding
cDNA
In genetics, complementary DNA (cDNA) is DNA that was reverse transcribed (via reverse transcriptase) from an RNA (e.g., messenger RNA or microRNA). cDNA exists in both single-stranded and double-stranded forms and in both natural and engin ...
encoded for a protein with 359 amino acids and molecular mass of 40,276 daltons.
The receptor is a heterotrimeric
G protein-coupled receptor
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related ...
, 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
In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
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.
Signal transduction pathway
A 2014 journal article described that the PGD
2 receptor signaling pathway begins with the binding of prostaglandin D
2.
After PDG2 binds to the extracellular ligand site on the receptor, the G
s alpha subunit is activated. Activation of the G
s alpha subunit prompts activation of the enzyme
adenylate cyclase
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
, which is located on the cell membrane. Adenylate cyclase then catalyzes the change from ATP to
cyclic AMP
Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine triph ...
, or cAMP. The result of the PDG
2 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 PDG
2 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 PDG
2 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 PDG
2 receptor subtypes.
Disease relevance
Inflammation: PTGDR1 signaling results in many non-inflammatory effects, such as inhibition of
dendritic cell
A dendritic cell (DC) is an antigen-presenting cell (also known as an ''accessory cell'') of the mammalian immune system. A DC's main function is to process antigen material and present it on the cell surface to the T cells of the immune system ...
and
Langerhans cell
A Langerhans cell (LC) is a tissue-resident macrophage of the skin once thought to be a resident dendritic cell. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in t ...
migration and
eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along wi ...
apoptosis. PTGDR2 mediates several pro-inflammatory effects, including the stimulation of
TH2 cells,
ILC2
ILC2 cells, or type 2 innate lymphoid cells are a type of innate lymphoid cell. Not to be confused with the ILC. They are derived from common lymphoid progenitor and belong to the lymphoid lineage. These cells lack antigen specific B or T cell r ...
, and eosinophils.
Asthma: Activation of PTGDR2 amplifies an inflammation cascade by upregulating the expression and release of
type 2 cytokines through T
H2 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.
Neurodegeneration: A 2018 study induced the prostaglandin D
2 signaling pathway in mice via PTGDR2 to determine the impact on
Parkinson's Disease
Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
-like pathology.
The researchers observed that the mice with PG treatment developed loss of dopamine neurons in the
substantia nigra pars compacta
The pars compacta (SNpc, SNc) is one of two subdivisions of the ''substantia nigra'' of the midbrain (the other being the pars reticulata); it is situated medial to the ''pars reticulata''. It is formed by dopaminergic neurons. It projects to t ...
, motor deficits, and other progressive disease-like symptoms. They also discovered PGD
2 receptors on dopaminergic cells but not on microglia.
See also
*
Eicosanoid receptor
Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that receptor (biochemistry), bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and theref ...
*
Prostaglandin E2 receptor
References
External links
*
{{Prostanoidergics
Eicosanoids
G protein-coupled receptors