HGNC Approved Gene Symbol: PTGER1
Cytogenetic location: 19p13.12 Genomic coordinates (GRCh38): 19:14,472,466-14,475,354 (from NCBI)
Prostaglandin E2 (PGE2) is involved in a number of physiologic and pathophysiologic events in many tissues of the body. The biologic effects of PGE2 are mediated through interaction with specific membrane-bound G protein-coupled prostanoid EP receptors. Subtypes of the EP receptor, termed EP1 (PTGER1), EP2 (PTGER2; 176804), EP3 (PTGER3; 176806), and EP4 (PTGER4; 601586), are defined on the basis of their pharmacologic profiles and signal transduction pathways and reviewed by Coleman et al. (1994).
From a human erythroleukemia cell cDNA library, Funk et al. (1993) isolated a functional cDNA clone coding for PTGER1. They found that PTGER1 comprises 402 amino acids with a predicted molecular mass of 41,858 and has the 7 predicted transmembrane-spanning domains common to all G protein-coupled receptors.
In their review, Sugimoto and Narumiya (2007) summarized findings on EP receptor expression gained through Northern blot analysis of mouse tissues and in situ hybridization of mouse kidney. They stated that mouse Ep1 mRNA was expressed predominantly in kidney. Within mouse kidney, Ep1 localized to renal papillary collecting ducts.
Funk et al. (1993) found that PTGER1 was functionally coupled to an increase in intracellular calcium ion when expressed in Xenopus oocytes.
In their review, Sugimoto and Narumiya (2007) stated that mouse Ep1 mediates PGE2-induced elevation of free calcium concentration in Chinese hamster ovary cells in a manner dependent on extracellular calcium, but not phosphatidylinositide.
Duncan et al. (1995) mapped the PTGER1 gene to chromosome 19p13.1 by in situ hybridization.
To identify the physiologic role of the EP1 receptor, Stock et al. (2001) generated Ep1 -/- mice using homologous recombination in embryonic stem cells. The Ep1 -/- mice were healthy and fertile, without overt physical defects. However, their pain sensitivity responses, tested in 2 acute prostaglandin-dependent models, were reduced by approximately 50%. This reduction in the perception of pain was virtually identical to that achieved through pharmacologic inhibition of prostaglandin synthesis in wildtype mice using a cyclooxygenase inhibitor. In addition, systolic blood pressure was significantly reduced in Ep1 receptor-deficient mice and accompanied by increased renin-angiotensin activity, especially in males, suggesting a role for this receptor in cardiovascular homeostasis. Thus, the EP1 receptor for PGE2 plays a direct role in mediating algesia and in regulation of blood pressure.
Sickness evokes various neural responses, one of which is activation of the hypothalamo-pituitary-adrenal (HPA) axis. This response can be induced experimentally by injection of bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as interleukin-1 (IL1; see 147760). Matsuoka et al. (2003) noted that although prostaglandins had long been implicated in LPS-induced HPA axis activation, the mechanism downstream of the prostaglandins remained unsettled. By using mice lacking each of the 4 PGE receptors and each of the 4 prostaglandin receptors (EP1-EP4) and an EP1-selective antagonist, Matsuoka et al. (2003) showed that both EP1 and EP3 are required for adrenocorticotropic hormone release in response to LPS. These and other findings suggested that EP1- and EP3-mediated neuronal pathways converge at corticotropin-releasing hormone-containing neurons in the paraventricular nucleus of the hypothalamus to induce HPA axis activation during sickness.
Matsuoka et al. (2005) found that Ptger1-null mice showed behavioral inhibition, manifested as impulsive aggression with defective social interaction, impaired cliff avoidance, and an exaggerated acoustic startle response when under social or environmental stress. The phenotype was reproduced in wildtype mice by administration of an EP1-selective antagonist, whereas administration of an EP1 agonist suppressed electric shock-induced impulsive aggression. Dopamine turnover in the frontal cortex and striatum was increased in Ptger1-null mice, and administration of dopaminergic antagonists corrected their behavioral phenotype. Matsuoka et al. (2005) suggested that prostaglandin E2 acts through EP1 to control impulsive behavior under stress.
Coleman, R. A., Smith, W. L., Narumiya, S. VIII. International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharm. Rev. 46: 205-229, 1994. [PubMed: 7938166]
Duncan, A. M. V., Anderson, L. L., Funk, C. D., Abramovitz, M., Adam, M. Chromosomal localization of the human prostanoid receptor gene family. Genomics 25: 740-742, 1995. [PubMed: 7759114] [Full Text: https://doi.org/10.1016/0888-7543(95)80022-e]
Funk, C. D., Furci, L., FitzGerald, G. A., Grygorczyk, R., Rochette, C., Bayne, M. A., Abramovitz, M., Adam, M., Metters, K. M. Cloning and expression of a cDNA for the human prostaglandin E receptor EP-1 subtype. J. Biol. Chem. 268: 26767-26772, 1993. [PubMed: 8253813]
Matsuoka, Y., Furuyashiki, T., Bito, H., Ushikubi, F., Tanaka, Y., Kobayashi, T., Muro, S., Satoh, N., Kayahara, T., Higashi, M., Mizoguchi, A., Shichi, H., Fukuda, Y., Nakao, K., Narumiya, S. Impaired adrenocorticotropic hormone response to bacterial endotoxin in mice deficient in prostaglandin E receptor EP1 and EP3 subtypes. Proc. Nat. Acad. Sci. 100: 4132-4137, 2003. [PubMed: 12642666] [Full Text: https://doi.org/10.1073/pnas.0633341100]
Matsuoka, Y., Furuyashiki, T., Yamada, K., Nagai, T., Bito, H., Tanaka, Y., Kitaoka, S., Ushikubi, F., Nabeshima, T., Narumiya, S. Prostaglandin E receptor E1 controls impulsive behavior under stress. Proc. Nat. Acad. Sci. 102: 16066-16071, 2005. [PubMed: 16247016] [Full Text: https://doi.org/10.1073/pnas.0504908102]
Stock, J. L., Shinjo, K., Burkhardt, J., Roach, M., Taniguchi, K., Ishikawa, T., Kim, H.-S., Flannery, P. J., Coffman, T. M., McNeish, J. D., Audoly, L. P. The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure. J. Clin. Invest. 107: 325-331, 2001. [PubMed: 11160156] [Full Text: https://doi.org/10.1172/JCI6749]
Sugimoto, Y., Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 282: 11613-11617, 2007. [PubMed: 17329241] [Full Text: https://doi.org/10.1074/jbc.R600038200]