New Tricks for an Old Dog: Biased GPCR Agonism of a M4 Muscarinic Acetylcholine Receptor Antagonist in ASM 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). Since then, additional studies have indeed confirmed the M4 mAChR selectivity of PD 102807 (4). The current report by Tompkins and colleagues is unique as it is the first to demonstrate that PD 102807 can exert non-M4 activities by acting as a biased M3 mAChR ligand on the basis of a set of carefully designed experiments on HEK293 cells and hTERT-immortalized airway smooth muscle (ASM) cells. The choice of using immortalized ASM cells over the traditional primary cells could be called into question with respect to the physiological relevance. However, this cellular model represents the best option to study the function of M3 mAChR in ASM cells that otherwise would be impossible in primary cells because of the loss of the receptor expression (and hence function) (5). The authors have provided convincing arguments showing the ability of PD 102807 to trigger M3 mAChR-biased signaling in ASM cells by preferably activating M3-GRK2 and 3–β-arrestin–dependent pathways independently of the canonical M3-Gq/calcium signaling. Although these findings were derived from cell-based studies, there are a number of exciting lessons that can be drawn from their work (summarized in Figure 1).