Pathway Map Details
CFTR-dependent regulation of ion channels in Airway Epithelium (norm and CF)
Object list (links open in MetaCore):
IP3 receptor, ATP extracellular region, ENaC, Ca('2+) endoplasmic reticulum lumen, DAG, YAP1 (YAp65), K('+) extracellular region, G-protein alpha-q/11, Ca('2+) cytosol, Cl('-) extracellular region,
CFTR-dependent regulation of ion channels in Airway Epithelium (CF and norm)
Cystic fibrosis transmembrane regulator ( CFTR ) and Epithelial sodium channel ( ENaC ) are the principal rate-limiting steps for Cl - secretion and Na + absorption by ciliated airway epithelia. These opposing processes are the main determinants of periciliary layer depth, which must be maintained within a range that permits simultaneous mucociliary clearance and unimpeded gas flow in the airway lumen. The importance of CFTR - ENaC inhibition is documented in cystic fibrosis (CF) patients which suffer from airway obstruction and chronic infection that results from decreased mucociliary clearance secondary to missing CFTR and accelerated ENaC activity .
The regulation of the ENaC has been intensively studied and the issue of organ-level specificity for these regulatory pathways is well known. Whereas ENaC activity in kidney or colon is regulated in part by systemic levels of mineralocorticoids and their downstream effectors, ENaC regulation in normal airways is largely refractory to these 'global' signals. Rather, ENaC in the airways appears to be regulated by local signals (the main way - inhibition by CFTR ) that reflect the status of the airway surface liquid (ASL) compartment that bathes airway surfaces .
However, it remains unclear how CFTR inhibits normal ENaC activity. A number of mechanisms were proposed ranging from altered cellular trafficking of ENaC to direct protein/protein interactions remain under investigation , , . For example, coordinated regulation of CFTR and ENaC may involve a large dynamic signaling complex composed of EBP50, YES-associated protein-65 ( YAP65 ) and non-receptor tyrosine kinase YES. Probably, this complex mediates ENaC inhibition by WWP2 via adaptor protein WBP1 or NEDD4 E3 ubiquitin protein ligases , , .
DeltaF508 CFTR potentially retains transporter functionality, but it fails to fold into its native conformation, and, therefore, is selected for endoplasmic reticulum (ER)-associated degradation (ERAD) by molecular chaperones and associated proteins. As a result, it fails to inhibit ENaC .
One local signal that normal airway epithelia respond to by altering ENaC activity, is the concentration of purine nucleotides in the ASL compartment. Extracellular ATP binds to P2Y2 receptors, which couple via G-protein alpha q/11 to activate PLC-beta and stimulate rapid hydrolysis of Phosphatidyl inositol-4,5-bisphosphonated ( PtdIns(4,5)P2 ) into Diaglycerol ( DAG ) and Inositol-1,4,5-trisphosphate ( IP3 ). As PtdIns(4,5)P2 is necessary for normal channel gating, its depletiopn at the apical membrane inhibits ENaC , . .
P2Y2 activation is a perspective therapeutic target in CF. P2Y2 inhibits ENaC and activates Ca 2+ -dependent chloride channels (these channels appear to be regulated by CFTR as well). PLC-beta- generated IP3 activates Ca 2+ -dependent chloride channel (e.g., Chloride channel calcium activated 2 ( CLCA2 )  ). P2Y2 also activates Ca 2+ -dependent potassium channel SK4/IK1 on the basolateral membrane, thus promoting membrane hyperpolarization and generation of a loop current responsible for CFTR - mediated anion secretion , , .
Another ASL signal used by normal airways epithelia is the local concentration/activity of specific 'channel activating proteases'. It was shown that extracellular serine protease Prostasin activates ENaC by converting a 'silent' channel at the apical membrane into a channel that is actively gating between open and closed states. The level of endogenous antiproteases (for example, Hepatocyte growth factor activator inhibitors 1 and 2, HAI-1 and HAI-2 ) is also important for regulation of ENaC activity , , , , .
Inactive in a neutral pH, amiloride-sensitive cation channel 3 ( ASIC3 ) is expressed in pulmonary epithelia and may be strongly activated in acidic CF epithelia due to CFTR dysfunction ( CFTR and ASIC3 down-regulate each other). This could explain elevated Na + reabsorption in CF in the event of an acidic luminal pH expected to inhibit ENaC .
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