Prostaglandin EP1 receptor

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PTGER1
Identifiers
Aliases PTGER1, EP1, EP1 receptor, prostaglandin E receptor 1
External IDs MGI: 97793 HomoloGene: 738 GeneCards: PTGER1
Targeted by Drug
prostaglandin D2, alprostadil, dinoprostone, dinoprost, [[d:Q9254396|]], sulprostone, treprostinil, U46619[1]
RNA expression pattern
PBB GE PTGER1 207650 x at tn.png

PBB GE PTGER1 214391 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000955

NM_013641

RefSeq (protein)

NP_000946

NP_038669.1
NP_038669

Location (UCSC) Chr 19: 14.47 – 14.48 Mb Chr 8: 83.67 – 83.67 Mb
PubMed search [2] [3]
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).[4] 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.[5]

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).[6]

Expression[edit]

Studies in mice, rats, and guinea pigs have found EP1 Messenger 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.[7] 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.[5][8]

Ligands[edit]

Activating ligands[edit]

The following standard prostaglandins have the following relative potencies in binding to and activating EP1: PGE2PGE1>PGF2alpha>PGD2. The receptor binding affinity Dissociation constant Kd (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.[8][9]

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 Ki 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.[8]

Inhibiting ligands[edit]

SC51322 (Ki=13.8 nM), GW-848687 (Ki=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).[8]

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.[5] 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.[5][9][10] 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.[11]

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; 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.[5][11][12][13]

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.[8]

See also[edit]

References[edit]

  1. ^ "Drugs that physically interact with Prostaglandin E receptor 1 view/edit references on wikidata". 
  2. ^ "Human PubMed Reference:". 
  3. ^ "Mouse PubMed Reference:". 
  4. ^ "Entrez Gene: PTGER1 prostaglandin E receptor 1 (subtype EP1), 42kDa". 
  5. ^ a b c d e Woodward DF, Jones RL, Narumiya S (September 2011). "International Union of Basic and Clinical Pharmacology. LXXXIII: classification of prostanoid receptors, updating 15 years of progress". Pharmacological Reviews. 63 (3): 471–538. doi:10.1124/pr.110.003517. PMID 21752876. 
  6. ^ https://www.ncbi.nlm.nih.gov/gene/5731
  7. ^ Ricciotti E, FitzGerald GA (May 2011). "Prostaglandins and inflammation". Arteriosclerosis, Thrombosis, and Vascular Biology. 31 (5): 986–1000. doi:10.1161/ATVBAHA.110.207449. PMC 3081099Freely accessible. PMID 21508345. 
  8. ^ a b c d e Markovič T, Jakopin Ž, Dolenc MS, Mlinarič-Raščan I (January 2017). "Structural features of subtype-selective EP receptor modulators". Drug Discovery Today. 22 (1): 57–71. doi:10.1016/j.drudis.2016.08.003. PMID 27506873. 
  9. ^ a b Narumiya S, Sugimoto Y, Ushikubi F (October 1999). "Prostanoid receptors: structures, properties, and functions". Physiological Reviews. 79 (4): 1193–226. PMID 10508233. 
  10. ^ Korbecki J, Baranowska-Bosiacka I, Gutowska I, Chlubek D (2014). "Cyclooxygenase pathways". Acta Biochimica Polonica. 61 (4): 639–49. PMID 25343148. 
  11. ^ a b Moreno JJ (December 2016). "Eicosanoid receptors: Targets for the treatment of disrupted intestinal epithelial homeostasis". European Journal of Pharmacology. 796: 7–19. doi:10.1016/j.ejphar.2016.12.004. PMID 27940058. 
  12. ^ Matsuoka T, Narumiya S (August 2008). "The roles of prostanoids in infection and sickness behaviors". Journal of Infection and Chemotherapy. 14 (4): 270–8. doi:10.1007/s10156-008-0622-3. PMID 18709530. 
  13. ^ Matsuoka T, Narumiya S (September 2007). "Prostaglandin receptor signaling in disease". TheScientificWorldJournal. 7: 1329–47. doi:10.1100/tsw.2007.182. PMID 17767353. 

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.