Exploring the role of β2- and β3-adrenergic receptors in cystic fibrosis

Cystic fibrosis (CF) is an autosomal recessive disorder that affects multiple organs, with clinical manifestations, disease progression, and response to therapy varying among individuals. This effect is mainly caused by mutations in the gene encoding for the CF transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel. In recent decades, other genes and their allelic variants, beyond CFTR mutations, have been proposed as genetic modifiers of CF phenotype. For instance, different polymorphic β2-adrenergic receptor (β2AR) polymorphic variants have been reported in CF individuals and appear to influence correct receptor function. β2AR belongs to the βAR family, which includes three subtypes: β1AR, β2AR, and β3AR. These receptors are crucial G protein-coupled receptors (GPCRs) expressed in various cell types and serve as key modulators of cAMP production, making their function particularly relevant in CF pathophysiology. β2AR is abundantly expressed in airway epithelial and smooth muscle cells, and studies revealed that it plays a crucial role in modulating CFTR activity and smooth muscle contractility through cAMP signaling. For these reasons, β2-agonists are widely used in clinical healthcare to treat patients with obstructive airway disorders, including CF. Emerging evidence has also supported a role for β3AR, which is expressed in the canine and human bronchial epithelium and have been reported to enhance ciliary motility and regulate CFTR function, making it a potential therapeutic target in CF.