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

Area of Science:

• Pharmacology
• Cell Biology
• Respiratory Medicine

Background:

• G protein-coupled receptors (GPCRs) exhibit biased signaling, allowing for fine-tuned physiological responses beyond simple on/off states.
• M3 muscarinic acetylcholine receptors (mAChRs) are implicated in qualitative signaling, but specific biased ligands and their functions remain largely uncharacterized.

Purpose of the Study:

• To identify and characterize a biased M3 mAChR ligand.
• To investigate the signaling pathways and functional consequences of this biased ligand in human airway smooth muscle (ASM) cells.

Main Methods:

• Identification of PD 102807 as a biased M3 ligand.
• Assessment of β-arrestin recruitment and calcium mobilization.
• Analysis of AMP-activated protein kinase (AMPK) and acetyl-coenzyme A carboxylase (ACC) phosphorylation.
• Evaluation of Gq-dependent and Gq-independent signaling pathways.
• Investigation of transforming growth factor β (TGF-β)-mediated functions.

Main Results:

• PD 102807 induced M3-mediated β-arrestin recruitment but not calcium mobilization.
• PD 102807 inhibited methacholine-induced calcium mobilization in ASM cells.
• PD 102807 promoted Gq protein-independent, GRK/arrestin-dependent AMPK signaling.
• PD 102807 inhibited TGF-β-induced SMAD-Luc activity, α-smooth muscle actin expression, and ASM cell hypercontractility.

Conclusions:

• PD 102807 is a novel biased M3 ligand that selectively inhibits M3-transduced Gq signaling while promoting AMPK signaling via a Gq-independent, GRK/arrestin-dependent pathway.
• This biased signaling modulates ASM phenotype and contractile function, highlighting the therapeutic potential of exploiting M3 receptor pleiotropy.