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The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Uses its C-Terminus to Regulate the A2B Adenosine Receptor

Lookup NU author(s): Abi Marklew, Dr Michael Gray

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

CFTR is an apical membrane anion channel that regulates fluid homeostasis in many organs including the airways, colon, pancreas and sweat glands. In cystic fibrosis, CFTR dysfunction causes significant morbidity/mortality. Whilst CFTR's function as an ion channel has been well described, its ability to regulate other proteins is less understood. We have previously shown that plasma membrane CFTR increases the surface density of the adenosine 2B receptor (A2BR), but not of the beta 2 adrenergic receptor (beta 2AR), leading to an enhanced, adenosine-induced cAMP response in the presence of CFTR. In this study, we have found that the C-terminal PDZ-domain of both A2BR and CFTR were crucial for this interaction, and that replacing the C-terminus of A2BR with that of beta 2AR removed this CFTR-dependency. This observation extended to intact epithelia and disruption of the actin cytoskeleton prevented A2BR-induced but not beta 2AR-induced airway surface liquid (ASL) secretion. We also found that CFTR expression altered the organization of the actin cytoskeleton and PDZ-binding proteins in both HEK293T cells and in well-differentiated human bronchial epithelia. Furthermore, removal of CFTR's PDZ binding motif (Delta TRL) prevented actin rearrangement, suggesting that CFTR insertion in the plasma membrane results in local reorganization of actin, PDZ binding proteins and certain GPCRs.


Publication metadata

Author(s): Watson MJ, Lee SL, Marklew AJ, Gilmore RC, Gentzsch M, Sassano MF, Gray MA, Tarran R

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2016

Volume: 6

Print publication date: 01/01/2016

Online publication date: 09/06/2016

Acceptance date: 17/05/2016

Date deposited: 14/07/2016

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/srep27390

DOI: 10.1038/srep27390


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Funding

Funder referenceFunder name
MRC (UK) studentship
DK051870 GM000678NIH
CFF BOUCHE15RONIH
HL1108723NIH
HL108927NIH
P30DK065988NIH

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