GPCRs and arrestins in airways: implications for asthma

Abstract

The obstructive lung disease asthma is treated by drugs that target, either directly or indirectly, G protein-coupled receptors (GPCRs). GPCRs coupled to Gq are the primary mediators of airway smooth muscle (ASM) contraction and increased airway resistance, whereas the Gs-coupled beta-2-adrenoceptor (β2AR) promotes pro-relaxant signaling in and relaxation of ASM resulting in greater airway patency and reversal of life-threatening bronchoconstriction. In addition, GPCR-mediated functions in other cell types, including airway epithelium and hematopoietic cells, are involved in the control of lung inflammation that causes most asthma. The capacity of arrestins to regulate GPCR signaling, via either control of GPCR desensitization/resensitization or G protein-independent signaling, renders arrestins an intriguing therapeutic target for asthma and other obstructive lung diseases. This review will focus on the potential role of arrestins in those GPCR-mediated airway cell functions that are dysregulated in asthma.

Figure 1. β-arrestin2 specifically regulates the β₂AR signaling and function in ASM

β₂AR (A) but not m3 mAChR or EP2 receptor (B and not shown) signaling is augmented ASM cultures derived from ASM tissue from β-arrestin2 knockout mice. This increase in β₂AR is associated with an increased ability to relax carbachol-contracted ASM ex vivo (C) and in vivo (reflected in change in airway resistance; D). Data from Deshpande et al.(Deshpande et al., 2008) and reproduced with permission from FASEB Journal.

Figure 2. Arrestin control of ASM signaling that regulates ASM contraction

β-arrestin2, and possibly β-arrestin1, limits β₂AR signaling and the capacity of beta-agonists to antagonize Gq-mediated ASM contraction. Conversely, Gq-coupled receptor (e.g., m3 mAChR or CysLT1R) signaling is minimally/not affected by arrestins. Thus, global or selective arrestin targeting has the potential to preferentially increase b2AR signaling throughput and shift the balance of signaling resulting in reduced contractile tone.

Figure 3. β-arrestin2 is required for development of the Asthma Phenotype

OVA-treated Wild type mice (black bars) displayed a significant increase in (A) total BAL lung cells, eosinophils and lymphocytes as well as (B) airway hyperresponsiveness relative to saline-treated WT and β-arrestin2-KO mice (light and dark gray bars, respectively) and compared to OVA—treated β-arrestin2-KO mice (white bars). (C) Chemotaxis of β-arrestin2-KO T lymphocytes to macrophage-derived chemokine (MDC) was significantly impaired as was (D) the accumulation of lung CD3+ and CD4+ T cells. Data from Walker et al.(Walker et al., 2003) and reproduced with permission of J Clin Invest.

Figure 4. Pro- and anti-asthmatic effects linked to specific G protein-independent and dependent signaling, respectively

Proposed model by which qualitative signaling influences asthma pathogenesis. Based on studies by the Walker, DeFea, and Bond labs, G protein-dependent signaling mediated by either PAR2 or β₂AR receptors in various airway cell types (including ASM, airway epithelium, or invading hematopoietic cells) can result in inhibition of multiple indices of inflammation or direct relaxation of ASM, thus attenuating the asthma phenotype. Conversely, G protein-independent signaling mediated by arrestins promotes inflammation and associated airway hyperresponsiveness.