Review and feature article
Molecular mechanisms of β2-adrenergic receptor function, response, and regulation

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The human β2-adrenoceptor is a member of the 7-transmembrane family of receptors, encoded by a gene on chromosome 5, and widely distributed in the respiratory tract. Intracellular signaling after β2-adrenoceptor activation is largely affected through cyclic adenosine monophosphate and protein kinase A. Differences in the mechanism of interaction of short- and long-acting β2-agonists and the β2-receptor are reflected in the kinetics of airway smooth muscle relaxation and the onset and duration of bronchodilation in asthmatic patients. β-Adrenoceptor desensitization associated with prolonged β2-agonist activation differs depending on the cell type and is reflected in different profiles of clinical tolerance to chronic β2-agonist therapy. A number of genetic polymorphisms of the β2-receptor have been described that appear to alter the behavior of the receptor, including the response to β2-agonists. The synergy between the β2-receptor and the glucocorticoid receptor functions has implications for the combined use of β2-agonists and corticosteroids in the treatment of respiratory disease.

Section snippets

β2-Adrenoceptor structure and distribution

The human β-adrenoceptor gene is situated on the long arm of chromosome 5 and codes for an intronless gene product of approximately 1200 base pairs.1 The β-adrenoceptor is comprised of 413 amino acid residues of approximately 46,500 daltons. β-Adrenoceptors have been subdivided into at least 3 distinct groups, β1, β2, and β3, which are classically identified in cardiac, airway smooth muscle, and adipose tissue, respectively. There is a 65% to 70% homology between β13 and β2-receptors. This

β2-Receptor activation

There is now good evidence that β2-adrenoceptors oscillate between 2 forms, activated and inactivated, and that under resting conditions, these 2 forms are in equilibrium, with the inactivated state being predominant.2 The β2-receptor is in the activated form when it is associated with the α-subunit of the Gs protein, together with a molecule of guanosine triphosphate (GTP). The replacement of the GTP by guanosine diphosphate dramatically reduces the affinity of the α-subunit for the receptor,

β2-Receptor signaling pathways

It has been the accepted dogma since the 1960s that β2-receptor activation is mediated by increased intracellular cAMP levels.9 This is the result of stimulation of adenylate cyclase, which catalyzes the conversion of adenosine triphosphate into cAMP. The coupling of the β2-receptor to adenylate cyclase is affected through a trimeric Gs protein,10 consisting of an α-subunit (which stimulates adenylate cyclase) and βγ-subunits (which transduce other signals). cAMP levels are then regulated

β2-Receptor/agonist interactions

The regions of the β2-adrenoceptor protein important for β2-agonist binding and G protein coupling have been identified by using site-directed mutagenesis. The active site of the receptor with which β2-agonists must interact to exert their biologic effects is located approximately one third of the way (15Å) into the receptor core (Fig 1). It is generally agreed that the residues of critical importance with respect to agonist binding to the active site are aspartate residue 113 (counted from the

β2-Receptor desensitization

Associated with β2-adrenoceptor activation is the autoregulatory process of receptor desensitization. This process operates as a safety device to prevent overstimulation of receptors in the face of excessive β2-agonist exposure. Desensitization occurs in response to the association of the receptor with the agonist molecule. The mechanisms by which desensitization can occur consist of 3 main processes: (1) uncoupling of the receptors from adenylate cyclase, (2) internalization of uncoupled

Polymorphisms of the β2-adrenoceptor

A number of polymorphisms of the β2-receptor have recently been described that alter the behavior of the receptor after agonist exposure. The main clinical interest in these polymorphisms lies in the possibility that they might determine the extent to which the receptor downregulates in the airways and as such might modify bronchodilator responses. There are 2 genes for the β2-adrenoceptor, and therefore an individual can be homozygous or heterozygous for a given polymorphism.

Studies on the β2

Conclusion

β2-Adrenergic agonists are used widely as bronchodilators and also in combination therapy with inhaled corticosteroids in the treatment of respiratory diseases, such as asthma and chronic obstructive pulmonary disease. Knowledge of the function, response, and regulation of the β2-receptor is important to the clinician in interpreting patient response to both short- and long-acting β2-agonists. Similarly, an understanding of the mechanisms of receptor desensitization that might lead to tolerance

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    (Supported by an unrestricted educational grant from Genentech, Inc. and Novartis Pharmaceuticals Corporation)

    Series editors: William T. Shearer, MD, PhD, Lanny J. Rosenwasser, MD, and Bruce S. Bochner, MD

    Disclosure of potential conflict of interest: M. Johnson is employed by GlaxoSmithKline.

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