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Cooperativity of E‐prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle
Author(s) -
Michael James V.,
Gavrila Adelina,
Nayak Ajay P.,
Pera Tonio,
Liberato Jennifer R.,
Polischak Steven R.,
Shah Sushrut D.,
Deshpande Deepak A.,
Penn Raymond B.
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201801959r
Subject(s) - prostaglandin e2 receptor , receptor , prostanoid , agonist , microbiology and biotechnology , signal transduction , biology , endocrinology , chemistry , medicine , biochemistry
Prostaglandin E2 (PGE 2 ) 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, whereas PGE 2 appeared to preferentially signal via the EP4 receptor. Both singular EP2 and EP4 receptor agonists inhibited HASM proliferation, and combined EP2 and EP4 receptor agonism exhibited positive cooperativity in both chronic G s ‐mediated signaling and inhibiting HASM proliferation. These findings suggest both EP2 and EP4 are functionally important in HASM, and their combined targeting optimally inhibits airway smooth muscle proliferation.—Michael, J. V. Gavrila, A., Nayak, A. P., Pera, T., Liberato, J. R., Polischak, S. R., Shah, S. D., Deshpande, D. A., Penn, R. B. Cooperativity of E‐prostanoid receptor subtypes in regulating signaling and growth inhibition in human airway smooth muscle. FASEB J. 33, 4780–4789 (2019). www.fasebj.org