Reactive Oxygen Species as β2-Adrenergic Receptor Signal Transducers

Reactive oxygen species (ROS), which include superoxide (O2−), hydrogen peroxide (H2O2), and the hydroxyl radical (OH.), have traditionally been cast as cellular byproducts, having benefit only for their microbicidal properties, while causing cellular damage that can lead to pathophysiological conditions. The detrimental effects of ROS have been well-described in morbidities such as ischemia, neurodegeneration, aging and cardiovascular disorders. However, there is also mounting evidence over the past decade implicating ROS as important molecules in intracellular signal transduction, and in particular, signaling of G protein-coupled receptors (GPCRs). Stimulation of several GPCRs such as muscarinic acetylcholine, angiotensin II-1, dopamine D5, as well as the 5-HT1A and 5-HT2A serotonin receptors has been shown to either increase or decrease ROS generation with significant downstream signaling consequences, suggesting that GPCR-mediated ROS signaling may have an important role in homeostatic balance which may be altered in pathophysiological states. Since the β2- adrenergic receptor (β2AR) has served as a prototypical GPCR, much work has also been done in regard to the involvement of ROS on β2AR signaling. This review focuses on the general role of ROS as a β2AR signal promoter, discussing β2AR-induced ROS generation, the involvement of ROS in G protein-dependent and β-arrestin-dependent signaling, as well as the critical role of oxidants in stabilization of β2AR.