CFTR-dependent regulation of ion channels in Airway Epithelium (CF and
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
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 Ca2+-dependent chloride channels (these channels appear to be
regulated by CFTR as well).
activates Ca2+-dependent chloride channel (e.g., Chloride channel calcium
activated 2 (CLCA2) ).
P2Y2 also activates Ca2+-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
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