The biological and therapeutic activity of selective β₂-agonists are exerted through cell-surface β₂-adrenergic receptors, which belong to the super-family of the 7-transmembrane G protein-coupled receptors. β₂-adrenergic receptors are widely distributed, occurring not only in airway smooth muscle, but also, although at a lower extent, in other cells of the lungs, such as epithelial and endothelial cells, and also mast cells. The receptor structure is represented in Figure 4, in which aminoacidic residues involved both in agonist binding (red) and in G-protein coupling (blue) are highlighted.

Figure 4: Human β₂-receptor structure. In red are shown the 4 amino acid residues involved in β₂-agonist binding. Regions or specific domains involved in G protein coupling (blue), desensitisation (pink), and downregulation (orange) are indicated.

After agonist binding to the active site of the receptor, the associated G_s protein is transformed into its activated form, which then activates the enzyme adenylate cyclase. This process generates an increase in cyclic adenosine monophosphate (cAMP), which is the first messenger of a wide cascade series, whose sequential release leads to the final biological effects, first of all bronchodilation. With this regard, cAMP induces airway smooth muscle cells relaxation (Fig. 5) principally by inhibiting calcium ions (Ca²⁺) release from the intracellular pools, by reducing Ca²⁺ entry throughout the cell membrane and increasing Ca²⁺ sequestration, thus depriving cells of the necessary element for the activation of contracting fibres.⁶

Figure 5: Bronchodilator effect of β₂-agonists.