Local Regulation of Cystic Fibrosis Transmembrane Regulator and Epithelial Sodium Channel in Airway Epithelium

Abstract

Regulation of cystic fibrosis transmembrane regulator (CFTR) and epithelial sodium channel (ENaC) in airway epithelia strongly influences the rate of mucociliary clearance (MCC) by determining the volume of airway surface liquid. MCC increases in response to stimuli originating on the airway surface, and CFTR and ENaC in airway epithelia appear to be regulated by local rather than systemic signaling. Although all signals that regulate CFTR and ENaC in airways have not been identified, the release of nucleotides from airway epithelial cells exposed to physical stimuli initiates a series of events that coordinately favor increased MCC. These events include activation of adenosine A2B receptors that stimulate CFTR and P2Y2 receptors that inhibit ENaC. Together these actions result in an increased volume of airway surface liquid and increased MCC rates. Stimulation of CFTR by A(2B)AR uses protein kinase (PK) A signaling elements that are localized within the apical/subapical compartment, including G proteins, adenylyl cyclase, PKA-II, A-kinase anchoring proteins, and phosphodiesterases. Inhibition of ENaC by P2Y2 receptors appears to be mediated by phospholipase C-beta3, possibly through an effect on the levels of phosphatidylinositol 4,5-bisphosphonate in the apical membrane.

cAMP‐dependent protein kinase A and the dynamics of epithelial cell surface domains: Moving membranes to keep in shape

“…As a final example, activation of PKA enhances the apical surface-directed transport of the cystic fibrosis transmembrane conductance regulator (CFTR) (63)(64) .…”

A2B Adenosine Receptors Regulate the Mucus Clearance Component of the Lung's Innate Defense System

“…Airway surface liquid (ASL) height must be greater than or equal to 7 mm to keep mucus away from the epithelial surface to allow cilia to beat and maintain efficient mucus transport. This complex process is in part mediated by ADO, which activates cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl -secretion in human nasal epithelia in vivo and directly regulates both CFTR Cl -channels and the epithelial Na 1 channel (ENaC) in cultured airways (15)(16)(17). Removal of ADO, inhibition of ADO-R, or a lack of CFTR (i.e., in CF airway epithelia) all result in a failure to regulate ASL height to 7 mm and result in a decrease in ASL height to CF-like levels (i.e., z 3 mm) (5,18).…”

Acinar origin of CFTR-dependent airway submucosal gland fluid secretion

“…First, we reasoned that in CF glands, VIP/forskolin might stimulate fluid secretion from the acini via a non-CFTR-dependent mechanism, but the mucus might then be blocked by hyperabsorption in the ducts. We reasoned that ductal hyperabsorption and blockage could occur if the lack of functional CFTR in the CF ducts caused the epithelial Na ϩ channel (ENaC) in the duct to be hyperactive, as it does in airway surface cells (6,28). This latter possibility was recently rendered unlikely by experiments in which ENaC blockers were applied to normal and CF glands without increasing secretion in normal glands or rescuing secretion in CF glands (10).…”