G Protein βγ-Subunit Signaling Mediates Airway Hyperresponsiveness and Inflammation in Allergic Asthma

Abstract

Since the Gβγ subunit of Gi protein has been importantly implicated in regulating immune and inflammatory responses, this study investigated the potential role and mechanism of action of Gβγ signaling in regulating the induction of airway hyperresponsiveness (AHR) in a rabbit model of allergic asthma. Relative to non-sensitized animals, OVA-sensitized rabbits challenged with inhaled OVA exhibited AHR, lung inflammation, elevated BAL levels of IL-13, and increased airway phosphodiesterase-4 (PDE4) activity. These proasthmatic responses were suppressed by pretreatment with an inhaled membrane-permeable anti-Gβγ blocking peptide, similar to the suppressive effect of glucocorticoid pretreatment. Extended mechanistic studies demonstrated that: 1) corresponding proasthmatic changes in contractility exhibited in isolated airway smooth muscle (ASM) sensitized with serum from OVA-sensitized+challenged rabbits or IL-13 were also Gβγ-dependent and mediated by MAPK-upregulated PDE4 activity; and 2) the latter was attributed to Gβγ-induced direct stimulation of the non-receptor tyrosine kinase, c-Src, resulting in downstream activation of ERK1/2 and its consequent transcriptional upregulation of PDE4. Collectively, these data are the first to identify that a mechanism involving Gβγ-induced direct activation of c-Src, leading to ERK1/2-mediated upregulation of PDE4 activity, plays a decisive role in regulating the induction of AHR and inflammation in a rabbit model of allergic airway disease.

The Cellular and Molecular Basis of Bitter Tastant-Induced Bronchodilation

“…It remains to be determined whether the inhibition of Ca 2+ signaling by TAS2R activation is Gβγ isoform specific. Since Gβγ also mediates the ASM contractions induced by activation of M2R and γ-aminobutyric acid-B receptors [61],[62], our present findings suggested that Gβγ reversal of the rise in [Ca 2+ ] i caused by bronchoconstrictors is isoform specific, and is likely via Gβ3γ13 dimers, which are released upon activation of TAS2Rs [63]. Further studies using ASM cells with genetic deletions of these isoforms should facilitate studying this possibility.…”

Asthmatic airway hyperresponsiveness: the ants in the tree

“…11 chain (smMHC) combined with actomyosin filamentogenesis and cellular hypertrophy by transforming growth factor (TGF) b1 [33] and cardiotrophin-1 [34] are good examples. Upregulation of phosphodiesterase-4 activity induced by IL-13, which increases ASM contractility by decreasing the concentration of the relaxant cAMP, is another example [35]. Notably, these mechanisms are not mutually exclusive and the identification of common mechanisms is not out of sight, although more studies are clearly needed.…”

Salmeterol Efficacy and Bias in the Activation and Kinase-Mediated Desensitization of β2-Adrenergic Receptors

“…Furthermore, the data indicate that even with the 14-hour pretreatment, isoproterenol was still able to stimulate the receptor after the lag and cause further desensitization, as indicated by the turnover of cAMP reaching a plateau value between 10 and 30 minutes. Since downstream PKA activation of PDE is both rapid and prolonged and is accompanied by PDE induction as well (Xin et al, 2008;Nino et al, 2009Nino et al, , 2012, it is likely that the contribution of PDE was relatively constant over the time of isoproterenol stimulation, regardless of the time of salmeterol pretreatment. This is further supported by the similar IBMX-induced increase in cAMP levels after isoproterenol (10-30 minutes).…”