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Sphingosine-1-phosphate is a novel regulator of cystic fibrosis transmembrane conductance regulator (CFTR) activity

Malik, Firhan A.; Meissner, Anja LU ; Semenkov, Illya; Molinski, Steven; Pasyk, Stan; Ahmadi, Saumel; Bui, Hai H.; Bear, Christine E.; Lidington, Darcy and Bolz, Steffen Sebastian (2015) In PLoS ONE 10(6).
Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) attenuates sphingosine- 1-phosphate (S1P) signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK), establishing a potential feedback link. In Baby Hamster Kidney (BHK) cells expressing wild-type human CFTR, S1P (1μmol/L) attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P's inhibitory effect is rapid (within 30 seconds), transient and correlates with CFTR serine residue 737 (S737) phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019) and AMPK inhibition (80μmol/L Compound C or AMPK... (More)

The cystic fibrosis transmembrane conductance regulator (CFTR) attenuates sphingosine- 1-phosphate (S1P) signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK), establishing a potential feedback link. In Baby Hamster Kidney (BHK) cells expressing wild-type human CFTR, S1P (1μmol/L) attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P's inhibitory effect is rapid (within 30 seconds), transient and correlates with CFTR serine residue 737 (S737) phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019) and AMPK inhibition (80μmol/L Compound C or AMPK siRNA) attenuate S1P-stimluated (i) AMPK phosphorylation, (ii) CFTR S737 phosphorylation and (iii) CFTR activity inhibition. In BHK cells expressing the δF508 CFTR mutant (CFTRδF508), the most common mutation causing cystic fibrosis, both S1P receptor antagonism and AMPK inhibition enhance CFTR activity, without instigating discernable correction. In summary, we demonstrate that S1P/ AMPK signaling transiently attenuates CFTR activity. Since our previous work positions CFTR as a negative S1P signaling regulator, this signaling link may positively reinforce S1P signals. This discovery has clinical ramifications for the treatment of disease states associated with enhanced S1P signaling and/or deficient CFTR activity (e.g. cystic fibrosis, heart failure). S1P receptor/AMPK inhibition could synergistically enhance the efficacy of therapeutic strategies aiming to correct aberrant CFTR trafficking.

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author
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published
in
PLoS ONE
volume
10
issue
6
publisher
Public Library of Science
external identifiers
  • scopus:84937950714
ISSN
1932-6203
DOI
10.1371/journal.pone.0130313
language
English
LU publication?
no
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ac8468e1-3ce2-4f78-93c1-57576cef61ed
date added to LUP
2017-05-23 22:22:25
date last changed
2017-07-30 05:25:35
@article{ac8468e1-3ce2-4f78-93c1-57576cef61ed,
  abstract     = {<p>The cystic fibrosis transmembrane conductance regulator (CFTR) attenuates sphingosine- 1-phosphate (S1P) signaling in resistance arteries and has emerged as a prominent regulator of myogenic vasoconstriction. This investigation demonstrates that S1P inhibits CFTR activity via adenosine monophosphate-activated kinase (AMPK), establishing a potential feedback link. In Baby Hamster Kidney (BHK) cells expressing wild-type human CFTR, S1P (1μmol/L) attenuates forskolin-stimulated, CFTR-dependent iodide efflux. S1P's inhibitory effect is rapid (within 30 seconds), transient and correlates with CFTR serine residue 737 (S737) phosphorylation. Both S1P receptor antagonism (4μmol/L VPC 23019) and AMPK inhibition (80μmol/L Compound C or AMPK siRNA) attenuate S1P-stimluated (i) AMPK phosphorylation, (ii) CFTR S737 phosphorylation and (iii) CFTR activity inhibition. In BHK cells expressing the δF508 CFTR mutant (CFTR<sup>δF508</sup>), the most common mutation causing cystic fibrosis, both S1P receptor antagonism and AMPK inhibition enhance CFTR activity, without instigating discernable correction. In summary, we demonstrate that S1P/ AMPK signaling transiently attenuates CFTR activity. Since our previous work positions CFTR as a negative S1P signaling regulator, this signaling link may positively reinforce S1P signals. This discovery has clinical ramifications for the treatment of disease states associated with enhanced S1P signaling and/or deficient CFTR activity (e.g. cystic fibrosis, heart failure). S1P receptor/AMPK inhibition could synergistically enhance the efficacy of therapeutic strategies aiming to correct aberrant CFTR trafficking.</p>},
  articleno    = {130313},
  author       = {Malik, Firhan A. and Meissner, Anja and Semenkov, Illya and Molinski, Steven and Pasyk, Stan and Ahmadi, Saumel and Bui, Hai H. and Bear, Christine E. and Lidington, Darcy and Bolz, Steffen Sebastian},
  issn         = {1932-6203},
  language     = {eng},
  month        = {06},
  number       = {6},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Sphingosine-1-phosphate is a novel regulator of cystic fibrosis transmembrane conductance regulator (CFTR) activity},
  url          = {http://dx.doi.org/10.1371/journal.pone.0130313},
  volume       = {10},
  year         = {2015},
}