The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure
Jeffrey L. Stock, … , John D. McNeish, Laurent P. Audoly
Jeffrey L. Stock, … , John D. McNeish, Laurent P. Audoly
Published February 1, 2001
Citation Information: J Clin Invest. 2001;107(3):325-331. https://doi.org/10.1172/JCI6749.
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Article

The prostaglandin E2 EP1 receptor mediates pain perception and regulates blood pressure

Abstract

The lipid mediator prostaglandin E2 (PGE2) has diverse biological activity in a variety of tissues. Four different receptor subtypes (EP1–4) mediate these wide-ranging effects. The EP-receptor subtypes differ in tissue distribution, ligand-binding affinity, and coupling to intracellular signaling pathways. To identify the physiological roles for one of these receptors, the EP1 receptor, we generated EP1-deficient (EP1–/–) mice using homologous recombination in embryonic stem cells derived from the DBA/1lacJ strain of mice. The EP1–/– mice are healthy and fertile, without any overt physical defects. However, their pain-sensitivity responses, tested in two acute prostaglandin-dependent models, were reduced by approximately 50%. This reduction in the perception of pain was virtually identical to that achieved through pharmacological inhibition of prostaglandin synthesis in wild-type mice using a cyclooxygenase inhibitor. In addition, systolic blood pressure is 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.

Authors

Jeffrey L. Stock, Katsuhiro Shinjo, John Burkhardt, Marsha Roach, Kana Taniguchi, Toshihisa Ishikawa, Hyung-Suk Kim, Patrick J. Flannery, Thomas M. Coffman, John D. McNeish, Laurent P. Audoly

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Figure 1

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Generation of PGE2 EP1 receptor–deficient DBA/1lacJ mice. (a) Strategy t...
Generation of PGE2 EP1 receptor–deficient DBA/1lacJ mice. (a) Strategy to inactivate EP1 by homologous recombination in DBA/1lacJ ES cells. Restriction maps depicting EP1 gene-targeting vector (top), endogenous EP1 gene (middle), and the targeted EP1 allele (bottom) are shown. Restriction enzymes used for mapping were: B, BamH1; E, EcoR1; H, HindIII; K, Kpn1; S, SacI; Sp, Spe1; and X, XbaI. PGK-tk and PGK-neo were inserted in opposite orientation to the EP1 gene as depicted in targeting vector (top). (b) Southern blot analysis of EP1+/+ (wild-type), EP1+/– (heterozygotes), and EP1–/– (homozygous mutants) genotypes. Genomic DNA from mouse tail was isolated and digested with BamH1 and hybridized with the external XbaI/SacI probe. The insertion of the neomycin gene into the EP1 locus produces a shift from the approximately 20-kb endogenous BamH1 fragment to 12 kb. (c) Expression of EP1 mRNA in EP1–/– and EP1+/+ mice by RT-PCR analysis of lung (L), uterus (U), and kidney (K) RNA. Positive PCR product was observed in tissues from EP1+/+ mice; however, none was present in EP1–/– mouse tissues, confirming loss of EP1 expression. β-actin controls were performed confirming presence of intact RNA in all samples. (d) Western blot analysis of PKN expression in brain lysates isolated from EP1–/– (left) and EP1+/+ (right) mice demonstrates that brain PKN protein levels are not affected by the targeting of ptgerep1. (e) In situ hybridization of kidney sections from EP1+/+ (left) and EP1–/– (right) mice demonstrates EP1-specific (not PKN) tubular expression.