Beta-adrenergic Signaling
Update on current concepts of the molecular basis of β2-adrenergic receptor signaling,☆☆

https://doi.org/10.1067/mai.2002.129945Get rights and content

Abstract

The proposed manner by which β2-adrenergic receptors signal has dramatically changed from earlier concepts that centered on a lock-and-key mechanism in which the receptor acts as a simple switch. We now know that β2-adrenergic receptors spontaneously toggle to an activated state (R*) and that the equilibrium between R (the inactive state) and R* can be altered by ligands. In addition, the R* conformation is likely to consist of multiple subspecies that may favor certain signaling pathways or regulatory events. Changes in agonist structure alter the abundance of certain subspecies of R*. Indeed, multifunctional coupling is common with many G-protein-coupled receptors and can be modulated pharmacologically to attain specific outcomes. In addition to providing the basis for development of new β-agonists for unique signaling, these properties can be extended such that β2-adrenergic receptors, or highly modified “designer” receptors, can be used for gene therapy with highly specific effects. (J Allergy Clin Immunol 2002;110:S223-8.)

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).

. Amino acid sequence and proposed membrane topology of the human β2AR. Regions or specific domains with structural significance are labeled. TMD 1 and TMD 7 indicate the first and seventh transmembrane-spanning domains, respectively. βARK, β-AR kinase.

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.

. General mechanisms of multifunctional coupling of GPCRs. R, Receptor; G, G-protein α subunit; E, effector; NGT, non-G-protein transducer; 2nd MESS, second messenger.

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.

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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.

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