Pro-Relaxant EP Receptors Functionally Partition to Different Pro-Contractile Receptors in Airway Smooth Muscle
American Journal of Respiratory Cell and Molecular Biology(2023)
摘要
Prostaglandin E2 (PGE2) imparts diverse physiological effects on multiple airway cells through its actions on four distinct E-type prostanoid (EP) receptors (EP1-4). Gs-coupled EP2 and EP4 receptors are expressed on airway smooth muscle (ASM), yet their capacity to regulate ASM contractile state remains subject to debate. We used EP2 (ONO-259) and EP4 (ONO-329) subtype-specific agonists in cell- and tissue- based models of human ASM contraction (Magnetic Twisting Cytometry (MTC), and precision cut lung slices (PCLS), respectively) to study the EP2- and EP4- regulation of ASM contraction and signaling under conditions of histamine or methacholine (MCh) stimulation. ONO-329 was superior (<0.05) to ONO-259 in relaxing MCh-contracted PCLS (logEC50: 4.9e-07 vs. 2.2e-06; maximal bronchodilation 35± 2% S.E. vs. 15± 2% S.E.). However, ONO-259 and ONO-329 were similarly efficacious in relaxing histamine-contracted PCLS. Similar differential effects were observed in MTC studies. Signaling analyses revealed only modest differences in ONO-329- and ONO-259- induced phosphorylation of the PKA substrates VASP and HSP20 with concomitant stimulation with MCh or histamine. Conversely, ONO-259 failed to inhibit MCh- induced pMLC20 and the F/G actin ratio, while effectively inhibiting their induction by histamine. ONO-329 was effective in reversing induced pMLC20 and F/G actin by both MCh and histamine. Thus, the contractile-agonist-dependent differential effects are not explained by changes in the global levels of phosphorylated PKA substrates, but reflected in the regulation of pMLC20 (cross bridge cycling) and F/G actin ratio (actin cytoskeleton integrity, force transmission), implicating a role for compartmentalized signaling involving muscarinic, histamine, and EP receptor subtypes.
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关键词
airway smooth muscle,receptors,pro-relaxant,pro-contractile
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