Prostaglandin EP₃ receptor

Prostaglandin EP₃ receptor (53kDa), also known as EP₃, is a

Numerous synthetic compounds have been found to be highly selective in binding to but not stimulating EP₃. These Receptor antagonist DG-O41, L798,106, and ONO-AE3-240, block EP₃ from responding to PGE₂ or other agonists of this receptor, including Sulprostone, ONO-AE-248 and TEI-3356. They are in development primarily as anti-thrombotics, i.e. drugs to treat pathological blood clotting in humans.^[12]

Mechanism of cell activation

EP₃ is classified as an inhibitory type of prostanoid receptor based on its ability, upon activation, to inhibit the activation of

Studies using animals genetically engineered to lack EP₃ and supplemented by studies examining the actions of EP₃ receptor antagonists and agonists in animals as well as animal and human tissues indicate that this receptor serves various functions. However, an EP₃ receptor function found in these studies does not necessarily indicate that in does do in humans. For example, EP₃ receptor activation promotes duodenal secretion in mice; this function is mediated by EP₄ receptor activation in humans.[13] EP receptor functions can vary with species and most of the functional studies cited here have not translated their animal and tissue models to humans.

Digestive system

The secretion of HCO⁻
₃ (bicarbonate anion) from Brunner's glands of the duodenum serves to neutralize the highly acidified digestive products released from the stomach and thereby prevents ulcerative damage to the small intestine. Activation of EP₃ and EP₄ receptors in mice stimulates this secretion but in humans activation of EP₄, not EP₃, appears responsible for this secretion.^[13] These two prostanoid receptors also stimulate intestinal mucous secretion, a function which may also act to reduce acidic damage to the duodenum.^[14]

Fever

EP₃-deficient mice as well as mice selectively deleted of EP₃ expression in the brain's

In a mouse model of ovalbumin-induced asthma, a selective EP₃ agonist reduced airway cellularity, mucus, and bronchoconstriction responses to methacholine. In this model, EP₃-deficient mice, upon ovalbumin challenge, exhibited worsened allergic inflammation as measured by increased airway eosinophils, neutrophils, lymphocytes, and pro-allergic cytokines (i.e. interleukin 4, interleukin 5, and interleukin 13) as compared to wild type mice.^[7][17] EP₃ receptor-deficient mice and/or wild type mice treated with an EP₃ receptor agonist are similarly protected from allergic responses in models of allergic conjunctivitis and contact hypersensitivity.^[18] Thus, EP₃ appears to serve an important role in reducing allergic reactivity at least in mice.

Cough

Studies with mice, guinea pig, and human tissues and in guinea pigs indicate that PGE₂ operates through EP₃ to trigger cough responses. Its mechanism of action involves activation and/or sensitization of TRPV1 (as well as TRPA1) receptors, presumably by an indirect mechanism. Genetic polymorphism in the EP3 receptor (rs11209716^[19]), has been associated with ACE inhibitor-induce cough in humans.^[20][21] The use of EP₃ receptor antagonists may warrant study for the treatment of chronic cough in humans.^[22]

Blood pressure

Activation of EP₃ receptors contracts vascular beds including rat mesentery artery, rat tail artery, guinea-pig aorta, rodent and human pulmonary artery, and murine renal and brain vasculature. Mice depleted of EP₃ are partially protected from brain injury consequential to experimentally induced cerebral ischemia. Furthermore, rodent studies indicate that agonist-induced activation of EP₃ in the brain by intra-cerebroventricular injection of PGE₂ or selective EP₃ agonist cause hypertension; a highly selective EP₃ receptor antagonist blocked this PGE2-induced response. These studies, which examine a sympatho-excitatory response (i.e. responses wherein brain excitation such as stroke raises blood pressure) suggest that certain hypertension responses in humans are mediated, at least in part, by EP₃.^[23]

Vascular permeability

Model studies indicate that PG₂ (but not specific antigens or

• Misoprostol, an EP₃ and EP₄ receptor agonist, is in clinical use to prevent ulcers, to induce labor in pregnancy, medical abortion, and late miscarriage, and to prevent and treat postpartum bleeding (see Misoprostol).
• Sulprostone, relatively selective EP₃
  receptor agonist^[13] with a weak ability to stimulate the EP₁ receptor is in clinical use for inducing medical abortion and ending pregnancy after fetal death (see Sulprostone
  ).
• Raynauds disease, and scleroderma. Presumably, Iloprost works by stimulating EP₂, and EP₄ receptors which have vasodilation actions.^[32]

• duodenal ulcers.^[34]
• ONO-9054 (Sepetoprost), a dual an EP₃/
  open-angle glaucoma.^[35]
• DG-041, a highly selective EP₃ antagonist, has been proposed to warrant further study as anti-thrombosis agent.^[26][27]
• GR 63799X, MB-28767, ONO-AE-248, and TEI-3356 are putative EP₃ receptor-selective agonists that have been proposed to warrant further study to treat and/or prevent various types of cardiovascular diseases.^[12]

Genomic studies

The

• Eicosanoid receptor
• Prostaglandin E2 receptor 1 (EP1)
• Prostaglandin E2 receptor 2 (EP2)
• Prostaglandin E2 receptor 4 (EP4)

References