Biased Muscarinic Acetylcholine Receptor Signaling in Obstructive Lung Disease Pathology and Therapy

Thomas Jefferson University, Philadelphia PA

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Abstract

Project Summary G protein-coupled receptors (GPCRs) control important airway smooth muscle (ASM) cell functions including contraction, growth and phenotype that become dysregulated in obstructive lung diseases. Therefore, the clinical management of obstructive lung diseases such as asthma relies heavily of drugs that are either agonist or antagonists GPCRs. In this context, muscarinic receptor antagonists are used to relieve bronchoconstriction. Unfortunately, these drugs have limitations with respect to efficacy, and many patients experience suboptimal control. We have identified new, effective ligands that target the M3 muscarinic acetylcholine receptor (M3 mAChR) as a potential asthma therapy, by embracing the emerging concept of biased agonism. The pharmacology of biased agonism is based on the discovery that GPCRs can assume multiple conformations and interact with multiple proteins or protein complexes that transduce qualitatively different signals, and ligands can “tune” GPCRs to bias signaling and function to one pathway or another. We propose to discern biased signaling properties of the M3 mAChR and determine how GRK/arrestin-biased M3 signaling regulates ASM functions relevant to asthma. We have discovered two small molecule orthosteric ligands that can bias M3 mAChR signaling toward the GRK/arrestin signaling pathway. Our published and preliminary data indicate that arrestin-dependent signaling mediates therapeutically beneficial ASM functions such as inhibition of ASM cell contraction, proliferation and promotion of contractile phenotype. Supported by these observations, we hypothesize that arrestin-/GRK-dependent signaling by the M3 mAChR in ASM mediates multiple distinct beneficial signals and functions, and strategies that bias M3 mAChR signaling can be used to treat obstructive lung diseases. Biased M3 ligands will be tested in cell- and tissue-based studies of ASM signaling and function, and ultimately in an in vivo model of asthma to discern the efficacy of these biased M3 ligands as asthma therapeutics. Aim 1 studies will employ genetic, molecular and pharmacological strategies, including use of mice with arrestin subtype genes ablated, to establish how biased M3 ligands inhibit contractile signaling and promote relaxant signaling in ASM. Studies in Aim 2 will focus on anti-remodeling properties of biased M3 ligands and determine which mechanisms contribute to inhibition of ASM cell growth and modulation of ASM to a hypercontractile phenotype. Finally, Aim 3 studies will test our biased M3 ligands in an in vivo model of asthma to verify the ability of a biased ligand to mitigate features of allergic asthma. The impact of the proposed studies lies in their ability to significantly advance the science underlying, and ultimate clinical application of, biased agonism pharmacology to asthma.