Review and feature articleMolecular mechanisms of β2-adrenergic receptor function, response, and regulation
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 β1-β3 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.