CFTR (cystic fibrosis transmembrane conductance regulator) has been shown to form multiple protein macromolecular complexes with its interacting partners at discrete subcellular microdomains to modulate trafficking, transport and signalling in cells. Targeting protein–protein interactions within these macromolecular complexes would affect the expression or function of the CFTR channel. We specifically targeted the PDZ domain-based LPA2 (type 2 lysophosphatidic acid receptor)–NHERF2 (Na+/H+ exchanger regulatory factor-2) interaction within the CFTR–NHERF2–LPA2-containing macromolecular complexes in airway epithelia and tested its regulatory role on CFTR channel function. We identified a cell-permeable small-molecule compound that preferentially inhibits the LPA2–NHERF2 interaction. We show that this compound can disrupt the LPA2–NHERF2 interaction in cells and thus compromises the integrity of macromolecular complexes. Functionally, it elevates cAMP levels in proximity to CFTR and upregulates its channel activity. The results of the present study demonstrate that CFTR Cl− channel function can be finely tuned by modulating PDZ domain-based protein–protein interactions within the CFTR-containing macromolecular complexes. The present study might help to identify novel therapeutic targets to treat diseases associated with dysfunctional CFTR Cl− channels.
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Research Article|
March 29 2011
Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes: a small-molecule inhibitor approach
Weiqiang Zhang;
Weiqiang Zhang
*Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
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Himabindu Penmatsa;
Himabindu Penmatsa
*Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
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Aixia Ren;
Aixia Ren
*Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
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Chandanamali Punchihewa;
Chandanamali Punchihewa
†Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, U.S.A.
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Andrew Lemoff;
Andrew Lemoff
†Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, U.S.A.
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Bing Yan;
Bing Yan
†Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, U.S.A.
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Naoaki Fujii;
Naoaki Fujii
†Department of Chemical Biology & Therapeutics, St Jude Children's Research Hospital, Memphis, TN 38105, U.S.A.
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Anjaparavanda P. Naren
Anjaparavanda P. Naren
1
*Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, U.S.A.
1To whom correspondence should be addressed (email anaren@uthsc.edu).
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Publisher: Portland Press Ltd
Received:
October 20 2010
Revision Received:
February 02 2011
Accepted:
February 08 2011
Accepted Manuscript online:
February 08 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 435 (2): 451–462.
Article history
Received:
October 20 2010
Revision Received:
February 02 2011
Accepted:
February 08 2011
Accepted Manuscript online:
February 08 2011
Connected Content
This is a commentary on:
Targeting the regulation of CFTR channels
Citation
Weiqiang Zhang, Himabindu Penmatsa, Aixia Ren, Chandanamali Punchihewa, Andrew Lemoff, Bing Yan, Naoaki Fujii, Anjaparavanda P. Naren; Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes: a small-molecule inhibitor approach. Biochem J 15 April 2011; 435 (2): 451–462. doi: https://doi.org/10.1042/BJ20101725
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