PD 102807 Induces M3 mAChR-Dependent GRK-/Arrestin-Biased Signaling in Airway Smooth Muscle Cells

Interleukin 31 receptor α promotes smooth muscle cell contraction and airway hyperresponsiveness in asthma

“…10f ). To determine the dependency of CHRM3 in IL-31RA-driven calcium elevation, we assessed carbachol-driven calcium elevation in hTERT cell line 72, which expresses very low levels of CHRM3 52 , 53 . In support of our hypothesis, we observed a significant attenuation of carbachol-driven calcium elevation in hTERT line 72 cells transfected with either the control plasmid or the IL-31RA overexpression plasmid (Fig.…”

The biased M3 mAChR ligand PD 102807 mediates qualitatively distinct signaling to regulate airway smooth muscle phenotype

“…We previously demonstrated that stimulation of human ASM cells with M3 mAChR ligands results in AMPK activation via either canonical (Gq-dependent) or biased (GRK/arrestin-dependent) signaling pathways ( 22 ). In order to further delineate the mechanism of M3-mediated AMPK activation, we focused on known kinases upstream of AMPK: TAK1, STK11 (LKB1), and CaMKK.…”

“…Our previous studies have shown that PD 102807 and MCh both induce AMPK phosphorylation, albeit via different mechanisms and with different kinetic profiles. While the MCh-induced p-AMPK is mediated by Gq, the PD 102807-induced p-AMPK is mediated by GRK/arrestin ( 22 ). In addition, PD 102807 induces sustained AMPK phosphorylation, whereas MCh-induced AMPK phosphorylation wanes in a matter of minutes.…”

“…We recently identified PD 102807—an established M4 mAChR antagonist ( 20 , 21 )—as a biased M3 mAChR ligand ( 22 ). In M3 mAChR-expressing ASM cells, PD 102807 promotes arrestin recruitment to the M3 mAChR and GRK-dependent signaling with no effect on Gq-mediated activation of calcium signaling.…”

New Tricks for an Old Dog: Biased GPCR Agonism of an M4 Muscarinic Acetylcholine Receptor Antagonist in Airway Smooth Muscle Cells

“…In this issue of the Journal , Tompkins and colleagues (pp. 550–561 ) describe a novel pharmacological property of PD 102807 with potential clinical implications in obstructive lung diseases ( 1 ). Back in 1997, two different labs originally described PD 102807 as a selective M4 mAChR antagonist by combining radioligand binding assays in mAChR overexpressing Chinese hamster ovary cells and functional assays performed in various rodent tissues ( 2 , 3 ).…”