β2-adrenoceptor in obstructive airway diseases: Agonism, antagonism or both?

Figure 3 Acute and chronic inverse agonist treatment in obstructive airway diseases. It was shown in cell and animal models that acute treatment of β-blockers induced a partial agonist response that led to an increase in MUC5AC production viaβ-arrestin2 which serves as a multi-protein scaffold, activating ERK1/2 and p38 mitogen-activated protein kinase (MAPK), resulting in mucus hypersecretion and increased airway resistance response to methacholine. However, chronic treatment of β-blockers led to a reduction in mucus secretion, decreased airway hyperresponsiveness and reduced inflammation, through the non-canonical β-arrestin2-mediated signaling induced by inverse agonism of β₂-adrenoceptors[46]. The differential response could be due to the binding of ligand to a shallower secondary binding site exposed only when an adequate conformational state is obtained as proposed by Soriano-Ursúa et al^[44], however more work need to be done to validate the mechanism.