Asthma is a common, chronic disorder characterized by airway inflammation and airway smooth muscle (ASM) contraction leading to airway constriction. The ?2-adrenergic receptor (?2AR) is a G protein coupled receptor (GPCR) that promotes the reversal of airway constriction when activated, and is a critical drug target for asthma therapeutics. ?-agonists have been cornerstone therapies for asthma but long-term use of these drugs leads to desensitization of therapeutic response. This can cause severe adverse effects and an increased risk of sudden death during an asthma attack. Canonically, ?2AR signaling is mediated by initial interaction with the Gs protein followed by receptor phosphorylation and arrestin recruitment. Evidence shows that signaling through the Gs pathway promotes the relaxation of ASM, while arrestin binding promotes ?2AR internalization, desensitization of receptor response to ?-agonists, and pro-inflammatory signaling. Balanced agonists, like current ?- agonist drugs, activate both of these pathways, resulting in concurrent therapeutic and harmful effects. Studies from our lab and others indicate that biased agonists can differentially activate these pathways toward discrete physiological responses. It is our hypothesis that molecules that selectively promote signaling through the Gs pathway, while antagonizing arrestin recruitment would attenuate the adverse effects associated with ?-agonists currently prescribed for asthma. Gs-biased agonists and allosteric modulators of ?2AR will be characterized by cAMP production through the Gs pathway and arrestin recruitment to the receptor, and the downstream processes of receptor phosphorylation and internalization will be evaluated. The effects of Gs-biased ?2AR signaling on key contributors to the negative effects of ?-agonism, desensitization of cAMP production / airway contractility and inflammatory response, will be thoroughly assessed in vitro and in physiological models. The proposed work is designed to take advantage of recent insights into GPCR biology with the goal of developing Gs-biased ?2AR ligands with improved therapeutic properties.
The ?2-adrenergic receptor is a key target for asthma therapeutics - current ?2AR agonists activate multiple signaling pathways, leading to both therapeutic and harmful physiologic responses. Selectively activating a single pathway by biasing signaling through the receptor should promote therapeutic effects (e.g. reversal of bronchoconstriction) and attenuate harmful effects (e.g. desensitization of response to therapy). Characterizing and developing G protein-biased ?2AR ligands represents an avenue for improved asthma therapeutics with fewer adverse effects, and thereby addresses a critical area of unmet medical need.
