PTGER1
Identifiers
Aliases	PTGER1, EP1, EP1 receptor, prostaglandin E receptor 1
External IDs	MGI: 97793 HomoloGene: 738 GeneCards: PTGER1
Gene location (Human) Chr. Chromosome 19 (human)[1] Band 19p13.12 Start 14,472,466 bp[1] End 14,475,362 bp[1]
Gene location (Mouse) Chr. Chromosome 8 (mouse)[2] Band 8 C2|8 40.22 cM Start 83,666,678 bp[2] End 83,672,753 bp[2]
RNA expression pattern More reference expression data
Gene ontology Molecular function • prostaglandin receptor activity • G-protein coupled receptor activity • signal transducer activity • prostaglandin E receptor activity • D1 dopamine receptor binding Cellular component • integral component of membrane • plasma membrane • integral component of plasma membrane • membrane • intracellular Biological process • G-protein coupled receptor signaling pathway • response to lipopolysaccharide • signal transduction • adenylate cyclase-activating dopamine receptor signaling pathway • inflammatory response • adenylate cyclase-activating G-protein coupled receptor signaling pathway • positive regulation of cytosolic calcium ion concentration • negative regulation of gastric emptying Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	5731	19216
Ensembl	ENSG00000160951	ENSMUSG00000019464
UniProt	P34995	P35375
RefSeq (mRNA)	NM_000955	NM_013641
RefSeq (protein)	NP_000946	NP_038669
Location (UCSC)	Chr 19: 14.47 – 14.48 Mb	Chr 8: 83.67 – 83.67 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

Prostaglandin E₂ receptor 1 (EP₁) is a 42kDa prostaglandin receptor encoded by the PTGER1 gene. EP₁ is one of four identified EP receptors, EP₁, EP₂, EP₃, and EP₄ which bind with and mediate cellular responses principally to prostaglandin E₂) (PGE₂) and also but generally with lesser affinity and responsiveness to certain other prostanoids (see Prostaglandin receptors).^[5] Animal model studies have implicated EP₁ in various physiological and pathological responses. However, key differences in the distribution of EP₁ between these test animals and humans as well as other complicating issues make it difficult to establish the function(s) of this receptor in human health and disease.^[6]

Gene[edit]

The PTGER₁ gene is located on human chromosome 19 at position p13.12 (i.e. 19p13.12), contains 2 introns and 3 exons, and codes for a G protein coupled receptor (GPCR) of the rhodopsin-like receptor family, Subfamily A14 (see rhodopsin-like receptors#Subfamily A14).^[7]

Expression[edit]

Studies in mice, rats, and guinea pigs have found EP₁Messenger RNA and protein to be expressed in the papillary collecting ducts of the kidney, in the kidney, lung, stomach, thalamus, and in the dorsal root ganglia neurons as well as several central nervous system sites.^[8] However, the expression of EP₁ In humans, its expression appears to be more limited: EP₁ receptors have been detected in human mast cells, pulmonary veins, keratinocytes, myometrium, and colon smooth muscle.^[6][9]

Ligands[edit]

Activating ligands[edit]

The following standard prostaglandins have the following relative potencies in binding to and activating EP₁: PGE₂≥PGE1>PGF2alpha>PGD2. The receptor binding affinity Dissociation constant K_d (i.e. ligand concentration needed to bind with 50% of available EP₁ receptors) is ~20 nM and that of PGE1 ~40 for the mouse receptor and ~25 nM for PGE2 with the human receptor.^[9][10]

Because PGE₂ activates multiple prostanoid receptors and has a short half-life in vivo due to its rapidly metabolism in cells by omega oxidation and beta oxidation], metabolically resistant EP₁-selective activators are useful for the study of EP₁'s function and could be clinically useful for the treatment of certain diseases. Only one such agonist that is highly selective in stimulating EP₁ has been synthesized and identified, ONO-D1-OO4. This compound has a K_i inhibitory binding value (see Biochemistry#Receptor/ligand binding affinity) of 150 nM compared to that of 25 nM for PGE₂ and is therefore ~5 times weaker than PGE₂.^[9]

Inhibiting ligands[edit]

SC51322 (K_i=13.8 nM), GW-848687 (K_i=8.6 nM), ONO-8711, SC-19220, SC-51089, and several other synthetic compounds given in next cited reference are selective competitive antagonists for EP₁ that have been used for studies in animal models of human diseases. Carbacylin, 17-phenyltrinor PGE₁, and several other tested compounds are dual EP₁/EP₃ antagonists (most marketed prostanoid receptor antagonists exhibit poor receptor selectivity).^[9]

Mechanism of cell activation[edit]

When initially bound to PGE₂ or other stimulating ligand, EP₁ mobilizes G proteins containing the Gq alpha subunit (Gαq/11)-G beta-gamma complex. These two subunits in turn stimulate the Phosphoinositide 3-kinase pathway that raises cellular cytosolic Ca²⁺ levels thereby regulating Ca²⁺-sensitive cell signal pathways which include, among several others, those that promote the activation of certain protein kinase C isoforms.^[6] Since, this rise in cytosolic Ca²⁺ can also contract muscle cells, EP₁ has been classified as a contractile type of prostanoid receptor. The activation of protein kinases C feeds back to phosphorylate and thereby desensitizes the activated EP₁ receptor (see homologous desensitization but may also desensitize other types of prostanoid and non-prostanoid receptors (see heterologous desensitization). These desensitizations limit further EP₁ receptor activation within the cell.^[6][10][11] Concurrently with the mobilization of these pathways, ligand-activated EP₁ stimulates ERK, p38 mitogen-activated protein kinases, and CREB pathways that lead to cellular functional responses.^[12]

Function[edit]

Studies using animals genetically engineered to lack EP₁ and supplemented by studies using treatment with EP₁ receptor antagonists and agonists indicate that this receptor serves several functions. 1) It mediates hyperalgesia due to EP1₁ receptors located in the central nervous system but suppresses pain perception due to E₁ located on dorsal root ganglia neurons in rats. Thus, PGE₂ causes increased pain perception when administered into the central nervous system but inhibits pain perception when administered systemically^{[citation needed]}; 2) It promotes colon cancer development in Azoxymethane-induced and APC gene knockout mice. 3) It promotes hypertension in diabetic mice and spontaneously hypertensive rats. 4) It suppresses stress-induced impulsive behavior and social dysfunction in mice by suppressing the activation of Dopamine receptor D1 and Dopamine receptor D2 signaling. 5) It enhances the differentiation of uncommitted T cell lymphocytes to the Th1 cell phenotype and may thereby favor the development of inflammatory rather than allergic responses to immune stimulation in rodents. Studies with human cells indicate that EP₁ serves a similar function on T cells. 6) It may reduce expression of Sodium-glucose transport proteins in the apical membrane or cells of the intestinal mucosa in rodents.^{[6][12][13][14]}7) It may be differentially involved in etiology of acute brain injuries. Pharmacological inhibition or genetic deletion of EP₁ receptor produce either beneficial of deleterious effects in rodent models of neurological disorders such as ischemic stroke,^[15]epileptic seizure,^[16] surgically induced brain injury^[17] and traumatic brain injury.^[18]

Clinical studies[edit]

EP1 receptor antagonists have been studied clinically primarily to treat hyperalgesia. Numerous EP antagonists have been developed including SC51332, GW-848687X, a benzofuran-containing drug that have had some efficacy in treating various hyperalgesic syndromes in animal models. None have as yet been reported to be useful in humans.^[9]

See also[edit]

• Prostaglandin receptors


• Prostanoid receptors


• Prostaglandin E2 receptor 2 (EP2)


• Prostaglandin E2 receptor 3 (EP3)


• Prostaglandin E2 receptor 4 (EP4)


• Eicosanoid receptor

References[edit]

Further reading[edit]

External links[edit]

• 
  "Prostanoid Receptors: EP₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
  

This article incorporates text from the United States National Library of Medicine, which is in the public domain.