Abstract:
:The β2-adrenergic receptor (β2AR) is the prototypical member of the heptahelical G protein-coupled receptor (GPCR) superfamily and is well-known to elicit biological effects through both G protein-dependent and G protein-independent signaling cascades. Agonism of β2AR has been described to promote phosphorylation and activation of extracellular signal-regulated kinases (ERK1/2) via a G-protein/PKA pathway that transpires rapidly upon receptor agonism, as well as by a distinct β-arrestin-mediated pathway that occurs at later time points. We have previously shown that β2AR agonism promotes generation of intracellular reactive oxygen species (ROS) and that β2AR-associated G protein signaling is dependent on ROS formation. It has also been suggested that β2AR-mediated ROS generation occurs via recruitment of β-arrestins. In this study, we confirm the effects of β-arrestin on β2AR-induced ROS generation, and investigate the ROS-dependency of β-arrestin-linked β2AR signaling. In HEK293 cells, both coimmunoprecipitation and BRET studies reveal that ROS are vital for the physical interaction of β2AR with β-arrestin partner proteins. Using phosphorylation of ERK1/2 as a functional endpoint to assess the role of ROS in β2AR-β-arrestin signaling, our results show that inhibition of intracellular ROS abrogates both the β-arrestin and G protein-mediated phosphorylation of ERK1/2 upon agonism of β2AR. Importantly, both the G protein and β-arrestin components were reversed upon exogenous administration of ROS, suggesting a critical role for oxidants in stabilization of β2AR. Taken together, our data signify that ROS serve purposeful roles in stabilizing both G protein- and β-arrestin-mediated β2AR signaling in HEK293 cells.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Singh M,Moniri NHdoi
10.1016/j.bcp.2012.06.012subject
Has Abstractpub_date
2012-09-01 00:00:00pages
661-9issue
5eissn
0006-2952issn
1873-2968pii
S0006-2952(12)00410-8journal_volume
84pub_type
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