β2 Agonists

Abstract

History suggests β agonists, the cognate ligand of the β₂ adrenoceptor, have been used as bronchodilators for around 5,000 years, and β agonists remain today the frontline treatment for asthma and chronic obstructive pulmonary disease (COPD). The β agonists used clinically today are the products of significant expenditure and over 100 year's intensive research aimed at minimizing side effects and enhancing therapeutic usefulness. The respiratory physician now has a therapeutic toolbox of long acting β agonists to prophylactically manage bronchoconstriction, and short acting β agonists to relieve acute exacerbations. Despite constituting the cornerstone of asthma and COPD therapy, these drugs are not perfect; significant safety issues have led to a black box warning advising that long acting β agonists should not be used alone in patients with asthma. In addition there are a significant proportion of patients whose asthma remains uncontrolled. In this chapter we discuss the evolution of β agonist use and how the understanding of β agonist actions on their principal target tissue, airway smooth muscle, has led to greater understanding of how these drugs can be further modified and improved in the future. Research into the genetics of the β₂ adrenoceptor will also be discussed, as will the implications of individual DNA profiles on the clinical outcomes of β agonist use (pharmacogenetics). Finally we comment on what the future may hold for the use of β agonists in respiratory disease.

Keywords: Airway smooth muscle; Asthma; Cyclic AMP; Isoprenaline; β adrenoceptor; β agonists.

Figure 1. The classic β₂AR signalling pathway

Binding of β₂-agonist to β₂AR induces a conformational change allowing the α-subunit of the G-protein to dissociate and bind to adenylyl cyclase. Adenylyl cyclase is thus activated and catalyses the formation of cyclic AMP (cAMP) from ATP. cAMP molecules bind to PKA which induces the dissociation of the catalytic and regulatory subunitsfrom each other. Once released, the PKA catalytic subunits phosphorylate and hence activate myriad cellular targets which results in airway smooth muscle relaxation and hence bronchodilation.

Figure 2. The pros and cons of β₂AR activation

As shown in Figure 1, activation of the β₂AR induces bronchorelaxation (i.e. a beneficial effect) via its activation of the adenylyl cyclase-cAMP-PKA pathway. In this Figure, parallel deleterious effects are highlighted whereby the activation of β₂ARs are controlled by βarrestins. As shown in the left hand side pathway in this figure, following exposure to β₂ agonists, β₂ARs are phosphorylated by G Protein Coupled Receptor Kinases (GRKs) and rapidly desensitized meaning that regardless of continued β₂ agonist presence, cAMP production is diminished. GRK regulates β₂AR activity in part by uncoupling the β₂AR from the Gα subunit of the G protein but also by promoting the binding of βarrestin molecules to the β₂AR. βarrestin physically blocks further β₂AR and Gα subunit interaction and hence further prevents the beneficial, pro-relaxant signalling pathway shown in figure 1 and also, in shortened form, on the right hand side of this diagram. However, the GRK- and βarrestin-mediated effects on cAMP signalling are not the only deleterious effects. βarrestin acts as a scaffold protein bringing together other molecules and initiating signalling via pathways not involving G-proteins for example the MAPK pathway.