Journal of Allergy and Clinical Immunology
Beta-adrenergic SignalingUpdate on current concepts of the molecular basis of β2-adrenergic receptor signaling☆,☆☆
Section snippets
β2AR structure and function relationships
Like all GPCRs, the β2AR is a protein that has 7 transmembrane-spanning domains, an amino terminus that is extracellular, a carboxyl terminus that is intracellular, 3 interconnecting extracellular loops, and 3 intracellular loops (Fig 1). Primarily
The “activated” β2AR
Concepts concerning how agonists trigger GPCR signaling have changed markedly during the past few years. Early models were typified by the concept of a lock and key mechanism whereby agonists fit into the receptor, which induced a conformational change in the receptor protein, leading to G-protein coupling. Thus the receptor was considered to act as a simple switch. Multiple studies have now shown that this is not the case with β2AR and many other GPCRs.
The current concepts involve the notion
Multieffector coupling
Fig 3 shows some of the mechanisms that lead to multifunctional coupling of GPCRs. As Fig 3, A, indicates, two receptors that are highly homologous (subtypes) can couple to two different G proteins, and if a nonselective agonist is used, two different signals can be observed. An example is the stimulation of extracellular
Designer β2AR-like receptors for gene therapy
This concept suggests that agonists could be designed to provide highly specialized signaling through the β2AR. We therefore considered that perhaps an engineered receptor could be used for gene therapy in the lung. As discussed elsewhere in this supplement (see article by McGraw on page S236), we have previously shown with targeted transgenic mice that overexpression of β2AR in certain cell types of the lung confers therapeutic responses. When β2AR was overexpressed in Clara cells of the upper
Conclusions
Recent studies have elucidated new details about the mechanism by which β2AR and other GPCRs carry out signal transduction. These mechanisms can potentially be exploited to attain highly specific properties in new agonists, pharmacologic or genetic agents that are distal to the receptor, or modified receptors used for gene therapy.
Acknowledgements
We thank Esther Getz for manuscript preparation.
References (19)
- et al.
Conserved aspartic acid residues 79 and 113 of the β-adrenergic receptor have different roles in receptor function
J Biol Chem
(1988) - et al.
Identification of two serine residues involved in agonist activation of the β-adrenergic receptor
J Biol Chem
(1989) - et al.
Expanding roles for β-arrestins as scaffolds and adapters in GPCR signaling and trafficking
Curr Opin Cell Biol
(2001) - et al.
α2A/α2C-adrenergic receptor third loop chimera show that agonist interaction with receptor-subtype backbone establishes G protein-coupled receptor kinase phosphorylation
J Biol Chem
(2000) - et al.
Simultaneous coupling of α2-adrenergic receptors to two G-proteins with opposing effects: subtype-selective coupling of α2C10, α2C4 and α2C2 adrenergic receptors to Gi and Gs
J Biol Chem
(1992) - et al.
Transgenic overexpression of β2-adrenergic receptors in airway smooth muscle alters myocyte function and ablates bronchial hyperreactivity
J Biol Chem
(1999) - et al.
Modification of the β2-adrenergic receptor to engineer a receptor-effector complex for gene therapy
J Biol Chem
(2001) - et al.
Crystal structure of rhodopsin: a G protein-coupled receptor
Science
(2000) - et al.
Involvement of Asn-293 in stereospecific agonist recognition and in activation of the β2-adrenergic receptor
Proc Natl Acad Sci U S A
(1996)
Cited by (72)
The bitter taste receptor agonist-induced negative chronotropic effects on the Langendorff-perfused isolated rat hearts
2020, European Journal of PharmacologyNovel miRNA-based biomarker panel for detection β <inf>2</inf> -agonists in goats
2019, Food ChemistryCitation Excerpt :Their reaction with β2-adrenergic receptor (ADRB2) on cell membrane will change membranous formation to yield ATP-regulated protein complexes by substituting adenosine triphosphate (ATP) for guanosine diphosphate (GTP). The complexes will accelerate heartbeat rate, relax smooth muscles in the bronchus, uterus and intestines, and promote insulin release and glycogen decomposition (Liggett, 1999, 2002; Verhoeckx, Doornbos, Witkamp, van der Greef, & Rodenburg, 2006). Searching for effective biomarkers based on the mechanism of β2-agonists helps identify new drugs and improve supervision efficiency.
β2-Adrenoceptor signalling bias in asthma and COPD and the potential impact on the comorbidities associated with these diseases
2018, Current Opinion in PharmacologyNovel insights in β-adrenergic receptor signaling
2018, Encyclopedia of Endocrine DiseasesNon-obvious correlations to disease management unraveled by Bayesian artificial intelligence analyses of CMS data
2016, Artificial Intelligence in MedicineCitation Excerpt :However, the rich vasculature within the lungs enables systemic absorption of the β2-adrenergic agonists [42]. Thus, the physiological and pharmacological effect of β2-adrenergic agonists can be manifested systemically in multiple organ systems including heart, skeletal muscle, kidneys expressing receptors [42–44]. This study explores direct and indirect effects of β2-adrenergic agonists that might potentially lead to renal dysfunction.
- ☆
Supported by National Institutes of Health grants HL45967 and GM61376.
- ☆☆
Reprint requests: Stephen B. Liggett, MD, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Room G062, Cincinnati, OH 45267-0564.