Cooperativity of E-prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle

Prostaglandin E2 (PGE2) is produced in the airway during allergic lung inflammation and both promotes and inhibits features of asthma pathology. These mixed effects relate to 4 E-prostanoid (EP) receptor subtypes (EP1, 2, 3 and 4) expressed at different levels on different resident and infiltrating airway cells. Although studies have asserted both EP2 and EP4 expression in human airway smooth muscle (HASM), a recent study asserted EP4 to be the functionally dominant EP subtype in HASM. Herein, we employ recently-developed subtype-selective ligands to investigate singular or combined EP2 and EP4 receptor activation in regulating HASM signaling and proliferation. The subtype specificity of ONO-AE1-259-01 (EP2 agonist) and ONO-AE1-329 (EP4 agonist) was first demonstrated in human embryonic kidney 293 cells stably expressing different EP receptor subtypes. EP receptor knockdown and subtype-selective antagonists demonstrated EP2 and EP4 receptor responsiveness in HASM cells to the specific ONO compounds, where...