CFTR-dependent regulation of ion channels in Airway Epithelium (norm and CF)

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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 [1].

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 [2].

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 [3], [4], [5]. 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 [6], [7], [8].

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 [9].

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 [10], [11], [12]. [13].

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). PLC-beta-generated IP3 activates Ca2+-dependent chloride channel (e.g., Chloride channel calcium activated 2 (CLCA2) [14]). 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 [10], [11], [14].

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 [15], [16], [17], [18], [19].

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 [20].

References:

  1. Smith JJ, Karp PH, Welsh MJ
    Defective fluid transport by cystic fibrosis airway epithelia. The Journal of clinical investigation 1994 Mar;93(3):1307-11
  2. Huang P, Gilmore E, Kultgen P, Barnes P, Milgram S, Stutts MJ
    Local regulation of cystic fibrosis transmembrane regulator and epithelial sodium channel in airway epithelium. Proceedings of the American Thoracic Society 2004;1(1):33-7
  3. Kunzelmann K, Schreiber R, Nitschke R, Mall M
    Control of epithelial Na+ conductance by the cystic fibrosis transmembrane conductance regulator. Pflugers Archiv : European journal of physiology 2000 Jun;440(2):193-201
  4. Berdiev BK, Cormet-Boyaka E, Tousson A, Qadri YJ, Oosterveld-Hut HM, Hong JS, Gonzales PA, Fuller CM, Sorscher EJ, Lukacs GL, Benos DJ
    Molecular proximity of cystic fibrosis transmembrane conductance regulator and epithelial sodium channel assessed by fluorescence resonance energy transfer. The Journal of biological chemistry 2007 Dec 14;282(50):36481-8
  5. Donaldson SH, Boucher RC
    Sodium channels and cystic fibrosis. Chest 2007 Nov;132(5):1631-6
  6. Snyder PM, Olson DR, McDonald FJ, Bucher DB
    Multiple WW domains, but not the C2 domain, are required for inhibition of the epithelial Na+ channel by human Nedd4. The Journal of biological chemistry 2001 Jul 27;276(30):28321-6
  7. McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM
    Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel. American journal of physiology. Renal physiology 2002 Sep;283(3):F431-6
  8. Guggino WB, Stanton BA
    New insights into cystic fibrosis: molecular switches that regulate CFTR. Nature reviews. Molecular cell biology 2006 Jun;7(6):426-36
  9. Gelman MS, Kannegaard ES, Kopito RR
    A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator. The Journal of biological chemistry 2002 Apr 5;277(14):11709-14
  10. Devor DC, Pilewski JM
    UTP inhibits Na+ absorption in wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. The American journal of physiology 1999 Apr;276(4 Pt 1):C827-37
  11. Mall M, Wissner A, Gonska T, Calenborn D, Kuehr J, Brandis M, Kunzelmann K
    Inhibition of amiloride-sensitive epithelial Na(+) absorption by extracellular nucleotides in human normal and cystic fibrosis airways. American journal of respiratory cell and molecular biology 2000 Dec;23(6):755-61
  12. Pochynyuk O, Tong Q, Staruschenko A, Stockand JD
    Binding and direct activation of the epithelial Na+ channel (ENaC) by phosphatidylinositides. The Journal of physiology 2007 Apr 15;580(Pt. 2):365-72
  13. Ma HP, Chou CF, Wei SP, Eaton DC
    Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations. Pflugers Archiv : European journal of physiology 2007 Oct;455(1):169-80
  14. Mall M, Gonska T, Thomas J, Schreiber R, Seydewitz HH, Kuehr J, Brandis M, Kunzelmann K
    Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia. Pediatric research 2003 Apr;53(4):608-18
  15. Bridges RJ, Newton BB, Pilewski JM, Devor DC, Poll CT, Hall RL
    Na+ transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39-9437. American journal of physiology. Lung cellular and molecular physiology 2001 Jul;281(1):L16-23
  16. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE
    Regulation of the epithelial sodium channel by serine proteases in human airways. The Journal of biological chemistry 2002 Mar 8;277(10):8338-45
  17. Caldwell RA, Boucher RC, Stutts MJ
    Serine protease activation of near-silent epithelial Na+ channels. American journal of physiology. Cell physiology 2004 Jan;286(1):C190-4
  18. Tong Z, Illek B, Bhagwandin VJ, Verghese GM, Caughey GH
    Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line. American journal of physiology. Lung cellular and molecular physiology 2004 Nov;287(5):L928-35
  19. Tarran R, Trout L, Donaldson SH, Boucher RC
    Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. The Journal of general physiology 2006 May;127(5):591-604
  20. Su X, Li Q, Shrestha K, Cormet-Boyaka E, Chen L, Smith PR, Sorscher EJ, Benos DJ, Matalon S, Ji HL
    Interregulation of proton-gated Na(+) channel 3 and cystic fibrosis transmembrane conductance regulator. The Journal of biological chemistry 2006 Dec 1;281(48):36960-8

  1. Smith JJ, Karp PH, Welsh MJ
    Defective fluid transport by cystic fibrosis airway epithelia. The Journal of clinical investigation 1994 Mar;93(3):1307-11
  2. Huang P, Gilmore E, Kultgen P, Barnes P, Milgram S, Stutts MJ
    Local regulation of cystic fibrosis transmembrane regulator and epithelial sodium channel in airway epithelium. Proceedings of the American Thoracic Society 2004;1(1):33-7
  3. Kunzelmann K, Schreiber R, Nitschke R, Mall M
    Control of epithelial Na+ conductance by the cystic fibrosis transmembrane conductance regulator. Pflugers Archiv : European journal of physiology 2000 Jun;440(2):193-201
  4. Berdiev BK, Cormet-Boyaka E, Tousson A, Qadri YJ, Oosterveld-Hut HM, Hong JS, Gonzales PA, Fuller CM, Sorscher EJ, Lukacs GL, Benos DJ
    Molecular proximity of cystic fibrosis transmembrane conductance regulator and epithelial sodium channel assessed by fluorescence resonance energy transfer. The Journal of biological chemistry 2007 Dec 14;282(50):36481-8
  5. Donaldson SH, Boucher RC
    Sodium channels and cystic fibrosis. Chest 2007 Nov;132(5):1631-6
  6. Snyder PM, Olson DR, McDonald FJ, Bucher DB
    Multiple WW domains, but not the C2 domain, are required for inhibition of the epithelial Na+ channel by human Nedd4. The Journal of biological chemistry 2001 Jul 27;276(30):28321-6
  7. McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM
    Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel. American journal of physiology. Renal physiology 2002 Sep;283(3):F431-6
  8. Guggino WB, Stanton BA
    New insights into cystic fibrosis: molecular switches that regulate CFTR. Nature reviews. Molecular cell biology 2006 Jun;7(6):426-36
  9. Gelman MS, Kannegaard ES, Kopito RR
    A principal role for the proteasome in endoplasmic reticulum-associated degradation of misfolded intracellular cystic fibrosis transmembrane conductance regulator. The Journal of biological chemistry 2002 Apr 5;277(14):11709-14
  10. Devor DC, Pilewski JM
    UTP inhibits Na+ absorption in wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. The American journal of physiology 1999 Apr;276(4 Pt 1):C827-37
  11. Mall M, Wissner A, Gonska T, Calenborn D, Kuehr J, Brandis M, Kunzelmann K
    Inhibition of amiloride-sensitive epithelial Na(+) absorption by extracellular nucleotides in human normal and cystic fibrosis airways. American journal of respiratory cell and molecular biology 2000 Dec;23(6):755-61
  12. Pochynyuk O, Tong Q, Staruschenko A, Stockand JD
    Binding and direct activation of the epithelial Na+ channel (ENaC) by phosphatidylinositides. The Journal of physiology 2007 Apr 15;580(Pt. 2):365-72
  13. Ma HP, Chou CF, Wei SP, Eaton DC
    Regulation of the epithelial sodium channel by phosphatidylinositides: experiments, implications, and speculations. Pflugers Archiv : European journal of physiology 2007 Oct;455(1):169-80
  14. Mall M, Gonska T, Thomas J, Schreiber R, Seydewitz HH, Kuehr J, Brandis M, Kunzelmann K
    Modulation of Ca2+-activated Cl- secretion by basolateral K+ channels in human normal and cystic fibrosis airway epithelia. Pediatric research 2003 Apr;53(4):608-18
  15. Bridges RJ, Newton BB, Pilewski JM, Devor DC, Poll CT, Hall RL
    Na+ transport in normal and CF human bronchial epithelial cells is inhibited by BAY 39-9437. American journal of physiology. Lung cellular and molecular physiology 2001 Jul;281(1):L16-23
  16. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE
    Regulation of the epithelial sodium channel by serine proteases in human airways. The Journal of biological chemistry 2002 Mar 8;277(10):8338-45
  17. Caldwell RA, Boucher RC, Stutts MJ
    Serine protease activation of near-silent epithelial Na+ channels. American journal of physiology. Cell physiology 2004 Jan;286(1):C190-4
  18. Tong Z, Illek B, Bhagwandin VJ, Verghese GM, Caughey GH
    Prostasin, a membrane-anchored serine peptidase, regulates sodium currents in JME/CF15 cells, a cystic fibrosis airway epithelial cell line. American journal of physiology. Lung cellular and molecular physiology 2004 Nov;287(5):L928-35
  19. Tarran R, Trout L, Donaldson SH, Boucher RC
    Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. The Journal of general physiology 2006 May;127(5):591-604
  20. Su X, Li Q, Shrestha K, Cormet-Boyaka E, Chen L, Smith PR, Sorscher EJ, Benos DJ, Matalon S, Ji HL
    Interregulation of proton-gated Na(+) channel 3 and cystic fibrosis transmembrane conductance regulator. The Journal of biological chemistry 2006 Dec 1;281(48):36960-8

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