We conclude that cigarette smoke decreases the expression of CFTR gene, protein, and function in vitro and that acquired CFTR deficiency occurs in the nasal respiratory epithelium of cigarette smokers. We suggest that acquired CFTR deficiency may contribute to the physiopathology of cigarette-induced diseases such as chronic bronchitis.

It has been demonstrated previously that both the cystic fibrosis transmembrane conductance regulator (CFTR) and ␤2 adrenergic receptor (␤2AR) can bind ezrin͞radixin͞moesin-binding phosphoprotein 50 (EBP50, also referred to as NHERF) through their PDZ motifs. Here, we show that ␤2 is the major adrenergic receptor isoform expressed in airway epithelia and that it colocalizes with CFTR at the apical membrane. ␤2AR stimulation increases CFTR activity, in airway epithelial cells, that is glybenclamide sensitive. Deletion of the PDZ motif from CFTR uncouples the channel from the receptor both physically and functionally. This uncoupling is specific to the ␤2AR receptor and does not affect CFTR coupling to other receptors (e.g., adenosine receptor pathway). Biochemical studies demonstrate the existence of a macromolecular complex involving CFTR-EBP50-␤ 2AR through PDZ-based interactions. Assembly of the complex is regulated by PKA-dependent phosphorylation. Deleting the regulatory domain of CFTR abolishes PKA regulation of complex assembly. This report summarizes a macromolecular signaling complex involving CFTR, the implications of which may be relevant to CFTR-dysfunction diseases.